Methods of increasing tear production

ABSTRACT

Described herein are methods and pharmaceutical formulations for increasing tear production.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Application No.62/066,280, filed on Oct. 20, 2014, and U.S. Provisional Application No.62/100,844, filed on Jan. 7, 2015, both of which are herein incorporatedby reference in their entirety.

BACKGROUND OF THE INVENTION

Dry Eye Disease (“DED”) is a condition that affects millions of peopleworldwide. Approximately 40 million people in North America have someform of dry eye, and many millions more suffer worldwide. DED resultsfrom the disruption of the natural tear film on the surface of the eye,and can result in ocular discomfort, visual disturbance and a reductionin vision-related quality of life. Patients with severe cases of DED areat risk for serious ocular health deficiencies such as cornealulceration, and can experience a quality of life deficiency comparableto that of moderate-severe angina.

SUMMARY OF THE INVENTION

Provided herein, in some embodiments, is a method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor. Insome embodiments, is a method of increasing tear production, comprisingthe local administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and does not cross theblood-brain barrier in a pharmacologically relevant concentration. Insome embodiments is method of increasing tear production, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to atleast one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis a method of increasing tear production, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and is administered in an amount thatis not systemically bioavailable. In some embodiments is a method ofincreasing tear production, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired systemic side effects.

Provided herein, in some embodiments, is a method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is a method of increasingtear production, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired psychoactive sideeffects. In some embodiments is a method of increasing tear production,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and in anamount that does not result in undesired systemic side effects.

Further provided herein, in some embodiments, is a method of treatingdry eye, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor. Insome embodiments, is a method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and does not cross the blood-brainbarrier in a pharmacologically relevant concentration. In someembodiments is method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to at least one ofthe peripheral nicotinic acetylcholine receptor subtypes selected fromalpha3beta4, alpha4beta2, and alpha7. In some embodiments is a method oftreating dry eye, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of treating dry eye,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and in anamount that does not result in undesired psychoactive side effects. Insome embodiments is a method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired systemic side effects.

Further provided herein, in some embodiments, is a method of treatingdry eye, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is a method of treating dry eye,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is a method of treating dryeye, comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and isadministered in an amount that is not systemically bioavailable. In someembodiments is a method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired psychoactive side effects. In some embodiments is a methodof treating dry eye, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired systemicside effects.

Further provided herein, in some embodiments, is a method of improvingocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor. In some embodiments, is a method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andis administered in an amount that is not systemically bioavailable. Insome embodiments is a method of improving ocular discomfort, comprisingthe local administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and in an amount that doesnot result in undesired psychoactive side effects. In some embodimentsis a method of improving ocular discomfort, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired systemic side effects.

Further provided herein, in some embodiments, is a method of improvingocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is amethod of improving ocular discomfort, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds toat least one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis a method of improving ocular discomfort, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and is administered in an amount thatis not systemically bioavailable. In some embodiments is a method ofimproving ocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired systemic side effects.

Further provided herein, in some embodiments, is a method of improvingocular surface health, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is amethod of improving ocular surface health, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds toat least one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis a method of improving ocular surface health, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and is administered in an amount thatis not systemically bioavailable. In some embodiments is a method ofimproving ocular surface health, comprising the local administration ofa therapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of improving ocularsurface health, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired systemic side effects.

Further provided herein, in some embodiments, is a method of protectingthe ocular surface during environmentally challenging conditions,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and does notcross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist does not cross theblood-brain barrier in a pharmacologically relevant concentration andselectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and is administered in anamount that is not systemically bioavailable. In some embodiments is amethod of protecting the ocular surface during environmentallychallenging conditions, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and in an amount that doesnot result in undesired systemic side effects.

Further provided herein, in some embodiments, is a method of increasingmucin content on the ocular surface, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist selectively binds to the peripheral nicotinicacetylcholine receptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is amethod of increasing mucin content on the ocular surface, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist does not cross theblood-brain barrier in a pharmacologically relevant concentration andselectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a method of increasing mucin contenton the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of increasing mucincontent on the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of increasing mucincontent on the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired systemicside effects.

Further provided herein, in some embodiments, is a method of increasingthe amount or concentration of one or more lacrimal proteins on theocular surface, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is a method of increasing the amountor concentration of one or more lacrimal proteins on the ocular surface,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is a method of increasingthe amount or concentration of one or more lacrimal proteins on theocular surface, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andis administered in an amount that is not systemically bioavailable. Insome embodiments is a method of increasing the amount or concentrationof one or more lacrimal proteins on the ocular surface, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and in an amount that doesnot result in undesired psychoactive side effects. In some embodimentsis a method of increasing the amount or concentration of one or morelacrimal proteins on the ocular surface, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired systemic side effects. In some embodiments the lacrimalprotein is epithelial growth factor, lactoferin, lacritin, prolactin,adrenocorticotropic, leucine enkephalin, ALS2CL, ARHGEF19, KIAA1109,PLXNA1, POLG, WIPI1, ZMIZ2 or other proteins of the tear proteome.

Further provided herein, in some embodiments, is a method of enhancingtear clearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is a method of enhancing tearclearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is a method of enhancingtear clearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andis administered in an amount that is not systemically bioavailable. Insome embodiments is a method of enhancing tear clearance, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and in an amount that doesnot result in undesired psychoactive side effects. In some embodimentsis a method of enhancing tear clearance, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired systemic side effects.

In a further embodiment of any of the aforementioned embodiments, themethod further comprises the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. In a furtherembodiment of any of the aforementioned embodiments, the method furthercomprises the local administration of one or more substances thatprevent the entry or reduce the entry of the nicotinic acetylcholinereceptor into the desensitized state, or facilitate the recovery of thenicotinic acetylcholine receptor from the desensitized state. In someembodiments, the one or more substances are selected from protein kinaseC (PKC) or factors that upregulate or up-modulate PKC, cAMP-dependentprotein kinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments, the calcineurin inhibitoris selected from cyclosporine, pimecrolimus, and tacrolimus.

In a further embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is selected from nicotine,cytisine, epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418,ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987,LY-2087101, A85380, and 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is selected from a compounddisclosed in WO 2008/057938, WO 2009/111550, WO 2010/028011, or WO2010/028033, each of which is incorporated herein by reference.

In a further embodiment of any of the aforementioned embodiments, atleast 1 microgram of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In a further embodiment of any ofthe aforementioned embodiments, at least 5 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Ina further embodiment of any of the aforementioned embodiments, at least10 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments, at least 25 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments, at least 50micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments, at least 100 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments, at least250 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments, at least 500 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity.

In a further embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is administered at least oncedaily. In another embodiment of any of the aforementioned embodiments,the nicotinic acetylcholine receptor agonist is administered at leasttwice daily. In another embodiment of any of the aforementionedembodiments, the nicotinic acetylcholine receptor agonist isadministered for at least two days.

In a further embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is administered as needed. Inanother embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is administered as needed inresponse to symptoms. In another embodiment of any of the aforementionedembodiments, the timing or frequency of administration of the nicotinicacetylcholine receptor agonist is designed or adjusted to preventdesensitization of the nicotinic acetylcholine receptors.

In a further embodiment of any of the aforementioned embodiments, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a liquid, suspension, aerosol, gel, ointment, dry powder,cream, paste, lotion, or balm. In a further embodiment of any of theaforementioned embodiments, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by a syringe, dropper, bottlenebulizer, atomization pump, inhaler, powder spray device, vaporizer,patch, medicated stick, pipette, or jet of liquid.

In a further embodiment of any of the aforementioned embodiments, thetrigeminal nerve is activated. In a further embodiment, the anteriorethmoidal nerve is activated.

In a further embodiment of any of the aforementioned embodiments, thenasolacrimal reflex is activated.

Further provided herein, in some embodiments, is a pharmaceuticalformulation for local administration in the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that is notsystemically bioavailable. In some embodiments is a pharmaceuticalformulation for local administration in the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects. In some embodimentsis a pharmaceutical formulation for local administration in the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects. In someembodiments, the pharmaceutical formulation further comprises one ormore substances selected from protein kinase C (PKC) or factors thatupregulate or up-modulate PKC, cAMP-dependent protein kinase (PKA) orfactors that upregulate or up-modulate PKA, and calcineurin inhibitors.In some embodiments, the calcineurin inhibitor is selected fromcyclosporine, pimecrolimus, and tacrolimus. In some embodiments, thenicotinic acetylcholine receptor agonist is selected from nicotine,cytisine, epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418,ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987,LY-2087101, A85380, and 5-I-A85380. In some embodiments, the nicotinicacetylcholine receptor agonist is selected from a compound disclosed inWO 2008/057938, WO 2009/111550, WO 2010/028011, or WO 2010/028033. Insome embodiments, the nicotinic acetylcholine receptor agonistselectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments, the pharmaceutical formulationcomprises about 1 mg/mL of the nicotinic acetylcholine receptor agonist.In some embodiments, the pharmaceutical formulation comprises about 10mg/mL of the nicotinic acetylcholine receptor agonist. In someembodiments, the pharmaceutical formulation comprises at least 1microgram of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 5micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 10micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 25micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 50micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 100micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 250micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises at least 500micrograms of the nicotinic acetylcholine receptor agonist per dose. Insome embodiments, the pharmaceutical formulation comprises between 5micrograms and 1 gram of the nicotinic acetylcholine receptor agonistper dose. In some embodiments, the pharmaceutical formulation isadministered at least once daily. In some embodiments, thepharmaceutical formulation is administered at least twice daily. In someembodiments, the pharmaceutical formulation is administered for at leasttwo days. In some embodiments, the pharmaceutical formulation isadministered into the nasal cavity as a liquid, suspension, aerosol,gel, ointment, dry powder, cream, paste, lotion, or balm. In someembodiments, the pharmaceutical formulation is administered into thenasal cavity by a syringe, dropper, bottle nebulizer, atomization pump,inhaler, powder spray device, vaporizer, patch, medicated stick,pipette, or jet of liquid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows tear production in patients receiving OC-01 compared tobaseline and placebo.

FIG. 2 depicts patient reported symptoms of dry eye in patientsreceiving OC-01 versus placebo.

FIG. 3 depicts the visual analog scale (VAS) for patients to recordseverity of their symptoms.

DETAILED DESCRIPTION OF THE INVENTION

The etiology of DED is becoming increasingly well understood. DED isprogressive in nature, and fundamentally results from insufficient tearcoverage on the surface of the eye. This poor tear coverage preventshealthy gas exchange and nutrient transport for the ocular surface,promotes cellular desiccation and creates a poor refractive surface forvision. Poor tear coverage typically results from: 1) insufficientaqueous tear production from the lacrimal glands (e.g. secondary topost-menopausal hormonal deficiency, auto-immune disease, LASIK surgery,etc.), and/or 2) excessive evaporation of aqueous tear resulting fromdysfunction of the meibomian glands. Low tear volume causes ahyperosmolar environment that induces an inflamed state of the ocularsurface. This inflammatory response induces apoptosis of the surfacecells which in turn prevents proper distribution of the tear film on theocular surface so that any given tear volume is rendered less effective.This initiates a vicious cycle where more inflammation can ensue causingmore surface cell damage, etc. Additionally, the neural control loop,which controls reflex tear activation, is disrupted because the sensoryneurons in the surface of the eye are damaged. As a result, fewer tearsare secreted and a second vicious cycle develops that results in furtherprogression of the disease (fewer tears cause nerve cell loss, whichresults in fewer tears, etc.).

There is a wide spectrum of treatments for DED, however, none providessubstantial efficacy for treatment of the condition. Treatment optionsinclude: artificial tear substitutes, ointments, gels, warm compresses,environmental modification, topical cyclosporine, omega-3 fatty acidsupplements, punctal plugs and moisture chamber goggles. Patients withsevere disease may further be treated with punctal cautery, systemiccholinergic agonists, systemic anti-inflammatory agents, mucolyticagents, autologous serum tears, PROSE scleral contact lenses andtarsorrhaphy. Despite these treatment options, DED continues to beconsidered one of the most poorly treated diseases in ophthalmology.Accordingly, it would be desirable to have a more effective treatmentfor dry eye.

Nicotinic acetylcholine receptors are cholinergic receptors found in thecentral nervous system (CNS), peripheral nervous systems (PNS) andskeletal muscles. These receptors are ligand-gated ion channels withbinding sites for acetylcholine and other molecules. When a nicotinicacetylcholine receptor agonist binds to the receptor, it stabilizes theopen state of the ion channel allowing influx of cations such aspotassium, calcium and sodium ions.

Acting on the central nervous system, systemic nicotinic acetylcholinereceptor agonists agonist are gaining attention as drug candidates formultiple disorders such as Alzheimer's disease, Parkinson's disease,schizophrenia, attention-deficit hyperactivity disorder (ADHD), andnicotine addiction. However, systemic exposure of these central nervoussystem agents has been associated with a variety of undesiredpsychoactive side effects including anxiety, depression, andirritability.

Described herein are methods of treating ocular conditions and/orimproving ocular surface health comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor. In some embodiments the nicotinic acetylcholine receptoragonist binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments the nicotinic acetylcholine receptoragonist binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration and is administered in an amount that is not systemicallybioavailable. In some embodiments the nicotinic acetylcholine receptoragonist binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration and is administered in an amount that does not result inundesired psychoactive side effects. In some embodiments the nicotinicacetylcholine receptor agonist binds to the peripheral nicotinicacetylcholine receptor and does not cross the blood-brain barrier in apharmacologically relevant concentration and is administered in anamount that does not result in undesired systemic side effects.

Prolonged or repeat exposure to a stimulus often results in decreasedresponsiveness of that receptor toward a stimulus, termeddesensitization. It has been reported that, after prolonged nicotinicacetylcholine receptor exposure to an agonist, the agonist itself causesan agonist-induced conformational change in the receptor, resulting inreceptor desensitization.

Described herein are methods of treating ocular conditions and/orimproving ocular surface health comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor, further comprising the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. Also describedherein are methods of treating ocular conditions and/or improving ocularsurface health comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor,further comprising the local administration of one or more substancesthat prevent the entry or reduce the entry of the nicotinicacetylcholine receptor into the desensitized state, or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. In some embodiments, the one or more substances that prevent orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state are selected from protein kinase C (PKC) or factorsthat upregulate or up-modulate PKC, cAMP-dependent protein kinase (PKA)or factors that upregulate or up-modulate PKA, and calcineurininhibitors.

Further described herein are pharmaceutical formulations for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization. Also described herein are pharmaceutical formulationsfor local administration into the nasal cavity of an individual, furthercomprising one or more substances that prevent or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. Also described herein are pharmaceutical formulations for localadministration into the nasal cavity of an individual, furthercomprising one or more substances that prevent the entry or reduce theentry of the nicotinic acetylcholine receptor into the desensitizedstate, or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state. Also described herein arepharmaceutical formulations for local administration into the nasalcavity of an individual, further comprising one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state, wherein the one or more substancesare selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. Alsodescribed herein are pharmaceutical formulations for localadministration into the nasal cavity of an individual, furthercomprising one or more substances that prevent the entry or reduce theentry of the nicotinic acetylcholine receptor into the desensitizedstate, or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state, wherein the one or more substancesare selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors.

Increased Tear Production

Provided herein, in some embodiments, is a method of increasing tearproduction in a subject. In some embodiments, is a method of increasingtear production, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is methodof increasing tear production, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to atleast one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis method of increasing tear production, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha3beta4. Insome embodiments is method of increasing tear production, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist does not cross theblood-brain barrier in a pharmacologically relevant concentration andselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha4beta2. In some embodiments is method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha7. In some embodiments is a methodof increasing tear production, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of increasing tearproduction, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired psychoactive sideeffects. In some embodiments is a method of increasing tear production,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and in anamount that does not result in undesired systemic side effects. In someembodiments is a method of increasing tear production, furthercomprising the local administration of one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state. In some embodiments is a method ofincreasing tear production, further comprising the local administrationof one or more substances that prevent the entry or reduce the entry ofthe nicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state.

In some embodiments is a method of increasing tear production, furthercomprising the local administration of one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state selected from protein kinase C(PKC) or factors that upregulate or up-modulate PKC, cAMP-dependentprotein kinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments is a method of increasingtear production, further comprising the local administration of one ormore substances that prevent the entry or reduce the entry of thenicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state selected from protein kinase C (PKC) or factors thatupregulate or up-modulate PKC, cAMP-dependent protein kinase (PKA) orfactors that upregulate or up-modulate PKA, and calcineurin inhibitors.In some embodiments is a method of increasing tear production, furthercomprising the local administration of protein kinase C (PKC) or factorsthat upregulate or up-modulate PKC. In some embodiments is a method ofincreasing tear production, further comprising the local administrationof cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA. In some embodiments is a method of increasing tearproduction, further comprising the local administration of a calcineurininhibitor. In some embodiments is a method of increasing tearproduction, further comprising the local administration of a calcineurininhibitor, wherein the calcineurin inhibitor is selected fromcyclosporine, pimecrolimus, and tacrolimus. In some embodiments is amethod of increasing tear production, further comprising the localadministration of cyclosporine. In some embodiments is a method ofincreasing tear production, further comprising the local administrationof pimecrolimus. In some embodiments is a method of increasing tearproduction, further comprising the local administration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is nicotine. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is cytisine. In another embodiment of anyof the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is epibatidine. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is varenicline.In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis tebanicline. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is DBO-83. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is CC4. In another embodiment of any ofthe aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is ABT-418. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is ABT-366833.In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis ABT-202. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is ABT-894. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is SIB-1663. In another embodiment of anyof the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is GTS-21. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis PNU-282987. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is LY-2087101. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is A85380. In another embodiment of anyof the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis selected from a compound disclosed in WO 2008/057938, WO 2009/111550,WO 2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 1 microgram of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 5 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 10 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 25 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 100 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 250 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 500 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, at least 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, between 1 microgram and 1000 micrograms ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing tear production, between 5 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing tear production, between 5micrograms and 100 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing tear production,between 5 micrograms and 50 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, between 10 micrograms and 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, between 25 micrograms and 1000 micrograms ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing tear production, between 50 micrograms and1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing tear production, between 100micrograms and 1000 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing tear production,between 100 micrograms and 750 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, between 150 micrograms and 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, between 150 micrograms and 600 micrograms ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered once daily. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered at least once daily. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered twice daily. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered at least twice daily. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered three times daily. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered at least three timesdaily. In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered for one day. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered for at least two days. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered for at least three days. In another embodiment of any ofthe aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is administered for at leastfour days. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered for at least five days. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is administeredfor at least seven days. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered for at least ten days. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered for at least fourteen days. In another embodiment of anyof the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is administered for at leasttwenty one days. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity as a liquid, suspension, aerosol,gel, ointment, dry powder, cream, paste, lotion, or balm. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a liquid. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa suspension. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as an aerosol. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity as a gel. In another embodiment ofany of the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as an ointment. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa dry powder. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a cream. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity as a paste. In another embodimentof any of the aforementioned embodiments of increasing tear production,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a lotion. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa balm.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by a syringe, dropper, bottlenebulizer, atomization pump, inhaler, powder spray device, vaporizer,patch, medicated stick, pipette, or jet of liquid. In another embodimentof any of the aforementioned embodiments of increasing tear production,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a syringe. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya dropper. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by a bottlenebulizer. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by an atomizationpump. In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by an inhaler. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a powder spray device. In another embodiment ofany of the aforementioned embodiments of increasing tear production, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a vaporizer. In another embodiment of any of theaforementioned embodiments of increasing tear production, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya patch. In another embodiment of any of the aforementioned embodimentsof increasing tear production, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a medicated stick. Inanother embodiment of any of the aforementioned embodiments ofincreasing tear production, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by a pipette. In anotherembodiment of any of the aforementioned embodiments of increasing tearproduction, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofincreasing tear production, the trigeminal nerve is activated. In afurther embodiment of increasing tear production, the anterior ethmoidalnerve is activated. In another embodiment of any of the aforementionedembodiments of increasing tear production, the nasolacrimal reflex isactivated.

Treating Dry Eye

Provided herein, in some embodiments, is a method of treating dry eye ina subject. In some embodiments, is a method of treating dry eye,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and does notcross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is method of treating dry eye,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is method of treating dryeye, comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha3beta4. In some embodiments ismethod of treating dry eye, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha4beta2. In someembodiments is method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha7. In someembodiments is a method of treating dry eye, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and is administered in an amount thatis not systemically bioavailable. In some embodiments is a method oftreating dry eye, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of treating dry eye,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and in anamount that does not result in undesired systemic side effects. In someembodiments is a method of treating dry eye, further comprising thelocal administration of one or more substances that prevent orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state. In some embodiments is a method of treating dry eye,further comprising the local administration of one or more substancesthat prevent the entry or reduce the entry of the nicotinicacetylcholine receptor into the desensitized state, or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. In some embodiments is a method of treating dry eye, furthercomprising the local administration of one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state selected from protein kinase C(PKC) or factors that upregulate or up-modulate PKC, cAMP-dependentprotein kinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments is a method of treating dryeye, further comprising the local administration of one or moresubstances that prevent the entry or reduce the entry of the nicotinicacetylcholine receptor into the desensitized state, or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. In someembodiments is a method of treating dry eye, further comprising thelocal administration of protein kinase C (PKC) or factors thatupregulate or up-modulate PKC. In some embodiments is a method oftreating dry eye, further comprising the local administration ofcAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA. In some embodiments is a method of treating dry eye,further comprising the local administration of a calcineurin inhibitor.In some embodiments is a method of treating dry eye, further comprisingthe local administration of a calcineurin inhibitor, wherein thecalcineurin inhibitor is selected from cyclosporine, pimecrolimus, andtacrolimus. In some embodiments is a method of treating dry eye, furthercomprising the local administration of cyclosporine. In some embodimentsis a method of treating dry eye, further comprising the localadministration of pimecrolimus. In some embodiments is a method oftreating dry eye, further comprising the local administration oftacrolimus.

In a further embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isselected from nicotine, cytisine, epibatidine, varenicline, tebanicline,DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21,PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is nicotine. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is cytisine. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is epibatidine. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is varenicline. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is tebanicline. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is DBO-83. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is CC4. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is ABT-418. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is ABT-366833. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is ABT-202. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is ABT-894. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is SIB-1663. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is GTS-21. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is PHA-543613. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is PNU-282987. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is LY-2087101. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is A85380. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isselected from a compound disclosed in WO 2008/057938, WO 2009/111550, WO2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, at least 1 microgram of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,at least 5 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of treating dry eye, at least 10 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of treating dry eye, at least 25 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, at least 50 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of treating dry eye, at least 100micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of treating dry eye, at least 250 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of treating dry eye, at least 500 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof treating dry eye, at least 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, at least 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 1 microgram and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 5 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 5 micrograms and 100 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 5 micrograms and 50 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 10 micrograms and 50 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 25 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 50 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,between 100 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, between 100 micrograms and 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, between 150 micrograms and 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, between 150 micrograms and 600 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered once daily. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered at least once daily. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, the nicotinic acetylcholine receptor agonist is administeredtwice daily. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered at least twice daily. In another embodiment ofany of the aforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered three times daily. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, the nicotinic acetylcholine receptor agonist is administered atleast three times daily. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered for one day. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered for atleast two days. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered for at least three days. In another embodimentof any of the aforementioned embodiments of treating dry eye, thenicotinic acetylcholine receptor agonist is administered for at leastfour days. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered for at least five days. In another embodiment ofany of the aforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered for at least seven days.In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered for at least ten days. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered for at least fourteendays. In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered for at least twenty one days. In another embodiment of anyof the aforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a liquid, suspension, aerosol,gel, ointment, dry powder, cream, paste, lotion, or balm. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a liquid. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa suspension. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as an aerosol. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a gel. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asan ointment. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a dry powder. Inanother embodiment of any of the aforementioned embodiments of treatingdry eye, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a cream. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa paste. In another embodiment of any of the aforementioned embodimentsof treating dry eye, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a lotion. In another embodiment ofany of the aforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa balm.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a syringe, dropper, bottlenebulizer, atomization pump, inhaler, powder spray device, vaporizer,patch, medicated stick, pipette, or jet of liquid. In another embodimentof any of the aforementioned embodiments of treating dry eye, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a syringe. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a dropper. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a bottle nebulizer. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity byan atomization pump. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by an inhaler. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a powder spray device. In another embodiment of any ofthe aforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya vaporizer. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a patch. In anotherembodiment of any of the aforementioned embodiments of treating dry eye,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a medicated stick. In another embodiment of any of theaforementioned embodiments of treating dry eye, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya pipette. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments oftreating dry eye, the trigeminal nerve is activated. In a furtherembodiment of treating dry eye, the anterior ethmoidal nerve isactivated. In another embodiment of any of the aforementionedembodiments of treating dry eye, the nasolacrimal reflex is activated.

Improved Ocular Discomfort

Provided herein, in some embodiments, is a method of improving oculardiscomfort in a subject. In some embodiments, is a method of improvingocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is methodof improving ocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to atleast one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis method of improving ocular discomfort, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha3beta4. Insome embodiments is method of improving ocular discomfort, comprisingthe local administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist does not cross theblood-brain barrier in a pharmacologically relevant concentration andselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha4beta2. In some embodiments is method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha7. In some embodiments is a methodof improving ocular discomfort, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of improving oculardiscomfort, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired psychoactive sideeffects. In some embodiments is a method of improving ocular discomfort,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist selectivelybinds to the peripheral nicotinic acetylcholine receptor and in anamount that does not result in undesired systemic side effects. In someembodiments is a method of improving ocular discomfort, furthercomprising the local administration of one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state. In some embodiments is a method ofimproving ocular discomfort, further comprising the local administrationof one or more substances that prevent the entry or reduce the entry ofthe nicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state. In some embodiments is a method of improving oculardiscomfort, further comprising the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state selected from proteinkinase C (PKC) or factors that upregulate or up-modulate PKC,cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of improving ocular discomfort, further comprising the localadministration of one or more substances that prevent the entry orreduce the entry of the nicotinic acetylcholine receptor into thedesensitized state, or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state selected from proteinkinase C (PKC) or factors that upregulate or up-modulate PKC,cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of improving ocular discomfort, further comprising the localadministration of protein kinase C (PKC) or factors that upregulate orup-modulate PKC. In some embodiments is a method of improving oculardiscomfort, further comprising the local administration ofcAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA. In some embodiments is a method of improving oculardiscomfort, further comprising the local administration of a calcineurininhibitor. In some embodiments is a method of improving oculardiscomfort, further comprising the local administration of a calcineurininhibitor, wherein the calcineurin inhibitor is selected fromcyclosporine, pimecrolimus, and tacrolimus. In some embodiments is amethod of improving ocular discomfort, further comprising the localadministration of cyclosporine. In some embodiments is a method ofimproving ocular discomfort, further comprising the local administrationof pimecrolimus. In some embodiments is a method of improving oculardiscomfort, further comprising the local administration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is nicotine. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is cytisine. In another embodiment of anyof the aforementioned embodiments of improving ocular discomfort, thenicotinic acetylcholine receptor agonist is epibatidine. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is varenicline.In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is tebanicline. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is DBO-83. In another embodiment of anyof the aforementioned embodiments of improving ocular discomfort, thenicotinic acetylcholine receptor agonist is CC4. In another embodimentof any of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is ABT-418. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is ABT-366833.In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is ABT-202. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is ABT-894. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is SIB-1663. In another embodiment of anyof the aforementioned embodiments of improving ocular discomfort, thenicotinic acetylcholine receptor agonist is GTS-21. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is PNU-282987. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is LY-2087101. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is A85380. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is selected from a compound disclosed in WO 2008/057938, WO2009/111550, WO 2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the ocular discomfort is associated withdry eye disease. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the ocular discomfort isassociated with the symptoms of dry eye disease. In another embodimentof any of the aforementioned embodiments of improving ocular discomfort,the ocular discomfort is associated with the symptoms of dry eyedisease; wherein the symptoms are selected from itchiness, dryness,photophobia, blurriness, pain, sticky feeling, burning, stinging, andforeign body sensation.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the ocular discomfort is associated withblepharitis. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the ocular discomfort isassociated with meibomian gland dysfunction. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,the ocular discomfort is associated with allergic conjunctivitis. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the ocular discomfort is associated with ocularsurface toxicity and irritation. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the oculardiscomfort is associated with lacrimal drainage problems. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the ocular discomfort is associated with eyelid disorders.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, at least 1 microgram of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, at least 5 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 10 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 25 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 50 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 100 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 250 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 500 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 750 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, at least 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, between 1 microgram and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, between 5 micrograms and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof improving ocular discomfort, between 5 micrograms and 100 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, between 5 micrograms and 50micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, between 10micrograms and 50 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,between 25 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, between 50 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, between 100 micrograms and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof improving ocular discomfort, between 100 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, between 150micrograms and 750 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,between 150 micrograms and 600 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered once daily. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered at least once daily. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered twice daily. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered at least twice daily. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered three times daily. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered at least three timesdaily. In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered for one day. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered for at least two days. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered for at least three days. In another embodiment of any ofthe aforementioned embodiments of improving ocular discomfort, thenicotinic acetylcholine receptor agonist is administered for at leastfour days. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is administered for at least five days. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is administeredfor at least seven days. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered for at least ten days. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered for at least fourteen days. In another embodiment of any ofthe aforementioned embodiments of improving ocular discomfort, thenicotinic acetylcholine receptor agonist is administered for at leasttwenty one days. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a liquid, suspension,aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a liquid. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a suspension. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asan aerosol. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a gel. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as an ointment. In another embodimentof any of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a dry powder. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa cream. In another embodiment of any of the aforementioned embodimentsof improving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a paste. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a lotion. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa balm.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a syringe, dropper,bottle nebulizer, atomization pump, inhaler, powder spray device,vaporizer, patch, medicated stick, pipette, or jet of liquid. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a syringe. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya dropper. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by a bottlenebulizer. In another embodiment of any of the aforementionedembodiments of improving ocular discomfort, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by an atomizationpump. In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by an inhaler. In anotherembodiment of any of the aforementioned embodiments of improving oculardiscomfort, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a powder spray device. In another embodiment ofany of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a vaporizer. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya patch. In another embodiment of any of the aforementioned embodimentsof improving ocular discomfort, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a medicated stick. Inanother embodiment of any of the aforementioned embodiments of improvingocular discomfort, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a pipette. In another embodimentof any of the aforementioned embodiments of improving ocular discomfort,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofimproving ocular discomfort, the trigeminal nerve is activated. In afurther embodiment of improving ocular discomfort, the anteriorethmoidal nerve is activated. In another embodiment of any of theaforementioned embodiments of improving ocular discomfort, thenasolacrimal reflex is activated.

Improved Ocular Surface Health

Provided herein, in some embodiments, is a method of improving ocularsurface health in a subject. In some embodiments, is a method ofimproving ocular surface health, comprising the local administration ofa therapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and does not cross the blood-brain barrier in apharmacologically relevant concentration. In some embodiments is methodof improving ocular surface health, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to atleast one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis method of improving ocular surface health, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha3beta4. Insome embodiments is method of improving ocular surface health,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha4beta2. In some embodiments ismethod of improving ocular surface health, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha7. In someembodiments is a method of improving ocular surface health, comprisingthe local administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and is administered in anamount that is not systemically bioavailable. In some embodiments is amethod of improving ocular surface health, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired psychoactive side effects. In some embodiments is a methodof improving ocular surface health, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist selectively binds to the peripheral nicotinicacetylcholine receptor and in an amount that does not result inundesired systemic side effects. In some embodiments is a method ofimproving ocular surface health, further comprising the localadministration of one or more substances that prevent or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. In some embodiments is a method of improving ocular surfacehealth, further comprising the local administration of one or moresubstances that prevent the entry or reduce the entry of the nicotinicacetylcholine receptor into the desensitized state, or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. In some embodiments is a method of improving ocular surfacehealth, further comprising the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state selected from proteinkinase C (PKC) or factors that upregulate or up-modulate PKC,cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of improving ocular surface health, further comprising the localadministration of one or more substances that prevent the entry orreduce the entry of the nicotinic acetylcholine receptor into thedesensitized state, or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state selected from proteinkinase C (PKC) or factors that upregulate or up-modulate PKC,cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of improving ocular surface health, further comprising the localadministration of protein kinase C (PKC) or factors that upregulate orup-modulate PKC. In some embodiments is a method of improving ocularsurface health, further comprising the local administration ofcAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA. In some embodiments is a method of improving ocularsurface health, further comprising the local administration of acalcineurin inhibitor. In some embodiments is a method of improvingocular surface health, further comprising the local administration of acalcineurin inhibitor, wherein the calcineurin inhibitor is selectedfrom cyclosporine, pimecrolimus, and tacrolimus. In some embodiments isa method of improving ocular surface health, further comprising thelocal administration of cyclosporine. In some embodiments is a method ofimproving ocular surface health, further comprising the localadministration of pimecrolimus. In some embodiments is a method ofimproving ocular surface health, further comprising the localadministration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is nicotine. In another embodiment of anyof the aforementioned embodiments of improving ocular surface health,the nicotinic acetylcholine receptor agonist is cytisine. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isepibatidine. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is varenicline. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is tebanicline. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, the nicotinic acetylcholine receptor agonist isDBO-83. In another embodiment of any of the aforementioned embodimentsof improving ocular surface health, the nicotinic acetylcholine receptoragonist is CC4. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is ABT-418. In another embodiment of anyof the aforementioned embodiments of improving ocular surface health,the nicotinic acetylcholine receptor agonist is ABT-366833. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist is ABT-202.In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is ABT-894. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is SIB-1663. In another embodiment of anyof the aforementioned embodiments of improving ocular surface health,the nicotinic acetylcholine receptor agonist is GTS-21. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isPHA-543613. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is PNU-282987. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is LY-2087101. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, the nicotinic acetylcholine receptor agonist isA85380. In another embodiment of any of the aforementioned embodimentsof improving ocular surface health, the nicotinic acetylcholine receptoragonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is selected from a compound disclosed in WO 2008/057938, WO2009/111550, WO 2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, at least 1 microgram of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 5 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 10 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 25 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 100 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 250 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 500 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, at least 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, between 1 microgram and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof improving ocular surface health, between 5 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, between 5micrograms and 100 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, between 5 micrograms and 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, between 10 micrograms and 50 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof improving ocular surface health, between 25 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, between50 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, between 100 micrograms and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof improving ocular surface health, between 100 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, between150 micrograms and 750 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, between 150 micrograms and 600 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered once daily. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered at least oncedaily. In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered twice daily. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered at least twicedaily. In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered three times daily. In another embodiment of anyof the aforementioned embodiments of improving ocular surface health,the nicotinic acetylcholine receptor agonist is administered at leastthree times daily. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered for one day. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isadministered for at least two days. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered for at leastthree days. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered for at least four days.In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered for at least five days. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is administered forat least seven days. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered for at least ten days. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, the nicotinic acetylcholine receptor agonist isadministered for at least fourteen days. In another embodiment of any ofthe aforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered for at leasttwenty one days. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a liquid, suspension,aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. Inanother embodiment of any of the aforementioned embodiments of improvingocular surface health, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a liquid. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a suspension. In another embodiment of any ofthe aforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as an aerosol. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa gel. In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as an ointment. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a dry powder. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a cream. In another embodiment ofany of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a paste. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a lotion. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa balm.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a syringe, dropper,bottle nebulizer, atomization pump, inhaler, powder spray device,vaporizer, patch, medicated stick, pipette, or jet of liquid. In anotherembodiment of any of the aforementioned embodiments of improving ocularsurface health, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a syringe. In another embodimentof any of the aforementioned embodiments of improving ocular surfacehealth, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a dropper. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a bottle nebulizer. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by an atomization pump. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by an inhaler. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya powder spray device. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a vaporizer. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a patch. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya medicated stick. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya pipette. In another embodiment of any of the aforementionedembodiments of improving ocular surface health, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya jet of liquid.

In another embodiment of any of the aforementioned embodiments ofimproving ocular surface health, the trigeminal nerve is activated. In afurther embodiment of improving ocular surface health, the anteriorethmoidal nerve is activated. In another embodiment of any of theaforementioned embodiments of improving ocular surface health, thenasolacrimal reflex is activated.

Protecting the Ocular Surface During Environmentally ChallengingConditions

Provided herein, in some embodiments, is a method of protecting theocular surface during environmentally challenging conditions in asubject. In some embodiments, is a method of protecting the ocularsurface during environmentally challenging conditions, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and does not cross theblood-brain barrier in a pharmacologically relevant concentration. Insome embodiments is method of protecting the ocular surface duringenvironmentally challenging conditions, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds toat least one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis method of protecting the ocular surface during environmentallychallenging conditions, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha3beta4. In someembodiments is method of protecting the ocular surface duringenvironmentally challenging conditions, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha4beta2. Insome embodiments is method of protecting the ocular surface duringenvironmentally challenging conditions, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha7. In someembodiments is a method of protecting the ocular surface duringenvironmentally challenging conditions, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and is administered in an amount thatis not systemically bioavailable. In some embodiments is a method ofprotecting the ocular surface during environmentally challengingconditions, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired psychoactive sideeffects. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and in an amount that doesnot result in undesired systemic side effects. In some embodiments is amethod of protecting the ocular surface during environmentallychallenging conditions, further comprising the local administration ofone or more substances that prevent or facilitate the recovery of thenicotinic acetylcholine receptor from the desensitized state. In someembodiments is a method of protecting the ocular surface duringenvironmentally challenging conditions, further comprising the localadministration of one or more substances that prevent the entry orreduce the entry of the nicotinic acetylcholine receptor into thedesensitized state, or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. In some embodimentsis a method of protecting the ocular surface during environmentallychallenging conditions, further comprising the local administration ofone or more substances that prevent or facilitate the recovery of thenicotinic acetylcholine receptor from the desensitized state selectedfrom protein kinase C (PKC) or factors that upregulate or up-modulatePKC, cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of protecting the ocular surface during environmentallychallenging conditions, further comprising the local administration ofone or more substances that prevent the entry or reduce the entry of thenicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state selected from protein kinase C (PKC) or factors thatupregulate or up-modulate PKC, cAMP-dependent protein kinase (PKA) orfactors that upregulate or up-modulate PKA, and calcineurin inhibitors.In some embodiments is a method of protecting the ocular surface duringenvironmentally challenging conditions, further comprising the localadministration of protein kinase C (PKC) or factors that upregulate orup-modulate PKC. In some embodiments is a method of protecting theocular surface during environmentally challenging conditions, furthercomprising the local administration of cAMP-dependent protein kinase(PKA) or factors that upregulate or up-modulate PKA. In some embodimentsis a method of protecting the ocular surface during environmentallychallenging conditions, further comprising the local administration of acalcineurin inhibitor. In some embodiments is a method of protecting theocular surface during environmentally challenging conditions, furthercomprising the local administration of a calcineurin inhibitor, whereinthe calcineurin inhibitor is selected from cyclosporine, pimecrolimus,and tacrolimus. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, furthercomprising the local administration of cyclosporine. In some embodimentsis a method of protecting the ocular surface during environmentallychallenging conditions, further comprising the local administration ofpimecrolimus. In some embodiments is a method of protecting the ocularsurface during environmentally challenging conditions, furthercomprising the local administration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is selectedfrom nicotine, cytisine, epibatidine, varenicline, tebanicline, DBO-83,CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21,PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is nicotine. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is cytisine. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is epibatidine. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is varenicline. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is tebanicline. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is DBO-83. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is CC4. In another embodimentof any of the aforementioned embodiments of protecting the ocularsurface during environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is ABT-418. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is ABT-366833. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is ABT-202. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is ABT-894. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is SIB-1663. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is GTS-21. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is PHA-543613. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is PNU-282987. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is LY-2087101. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is A85380. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is selectedfrom a compound disclosed in WO 2008/057938, WO 2009/111550, WO2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, at least 1 microgram of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, at least 5 micrograms ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, at least 10 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, at least 25 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, at least50 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, at least 100 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof protecting the ocular surface during environmentally challengingconditions, at least 250 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, at least500 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, at least 750 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof protecting the ocular surface during environmentally challengingconditions, at least 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, between 1microgram and 1000 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, between 5 micrograms and1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 5 micrograms and 100micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 5 micrograms and 50micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 10 micrograms and 50micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 25 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 50 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 100 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 100 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 150 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, between 150 micrograms and 600micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredonce daily. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered at least once daily. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered twice daily. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered at least twice daily. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredthree times daily. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered at least three times daily. In another embodiment of any ofthe aforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered for one day. In another embodiment ofany of the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered for at least two days. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredfor at least three days. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered for at least four days. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is administered for at leastfive days. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered for at least seven days. In another embodiment of any ofthe aforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered for at least ten days. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is administered for at leastfourteen days. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered for at least twenty one days. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredin alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a liquid, suspension, aerosol, gel, ointment,dry powder, cream, paste, lotion, or balm. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa liquid. In another embodiment of any of the aforementioned embodimentsof protecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a suspension. In another embodiment of any ofthe aforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as an aerosol. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a gel. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as an ointment.In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a dry powder. In another embodiment of any ofthe aforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a cream. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a paste. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a lotion. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a balm.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a syringe, dropper, bottle nebulizer,atomization pump, inhaler, powder spray device, vaporizer, patch,medicated stick, pipette, or jet of liquid. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya syringe. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a dropper. In another embodimentof any of the aforementioned embodiments of protecting the ocularsurface during environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya bottle nebulizer. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by an atomization pump. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by an inhaler. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a powder spray device. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a vaporizer. In another embodiment of any of theaforementioned embodiments of protecting the ocular surface duringenvironmentally challenging conditions, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by a patch. Inanother embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a medicated stick. In another embodiment of anyof the aforementioned embodiments of protecting the ocular surfaceduring environmentally challenging conditions, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya pipette. In another embodiment of any of the aforementionedembodiments of protecting the ocular surface during environmentallychallenging conditions, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofprotecting the ocular surface during environmentally challengingconditions, the trigeminal nerve is activated. In a further embodimentof protecting the ocular surface during environmentally challengingconditions, the anterior ethmoidal nerve is activated. In anotherembodiment of any of the aforementioned embodiments of protecting theocular surface during environmentally challenging conditions, thenasolacrimal reflex is activated.

Increasing Mucin Content on the Ocular Surface

Provided herein, in some embodiments, is a method of increasing mucincontent on the ocular surface in a subject. In some embodiments, is amethod of increasing mucin content on the ocular surface, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and does not cross theblood-brain barrier in a pharmacologically relevant concentration. Insome embodiments is method of increasing mucin content on the ocularsurface, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is method of increasingmucin content on the ocular surface, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha3beta4. In someembodiments is method of increasing mucin content on the ocular surface,comprising the local administration of a therapeutically effectiveamount of a nicotinic acetylcholine receptor agonist into the nasalcavity of an individual in need thereof, wherein the agonist does notcross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha4beta2. In some embodiments ismethod of increasing mucin content on the ocular surface, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist does not cross theblood-brain barrier in a pharmacologically relevant concentration andselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha7. In some embodiments is a method of increasing mucincontent on the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of increasing mucincontent on the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired psychoactiveside effects. In some embodiments is a method of increasing mucincontent on the ocular surface, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired systemicside effects. In some embodiments is a method of increasing mucincontent on the ocular surface, further comprising the localadministration of one or more substances that prevent or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate. In some embodiments is a method of increasing mucin content onthe ocular surface, further comprising the local administration of oneor more substances that prevent the entry or reduce the entry of thenicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state. In some embodiments is a method of increasing mucincontent on the ocular surface, further comprising the localadministration of one or more substances that prevent or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. In someembodiments is a method of increasing mucin content on the ocularsurface, further comprising the local administration of one or moresubstances that prevent the entry or reduce the entry of the nicotinicacetylcholine receptor into the desensitized state, or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. In someembodiments is a method of increasing mucin content on the ocularsurface, further comprising the local administration of protein kinase C(PKC) or factors that upregulate or up-modulate PKC. In some embodimentsis a method of increasing mucin content on the ocular surface, furthercomprising the local administration of cAMP-dependent protein kinase(PKA) or factors that upregulate or up-modulate PKA. In some embodimentsis a method of increasing mucin content on the ocular surface, furthercomprising the local administration of a calcineurin inhibitor. In someembodiments is a method of increasing mucin content on the ocularsurface, further comprising the local administration of a calcineurininhibitor, wherein the calcineurin inhibitor is selected fromcyclosporine, pimecrolimus, and tacrolimus. In some embodiments is amethod of increasing mucin content on the ocular surface, furthercomprising the local administration of cyclosporine. In some embodimentsis a method of increasing mucin content on the ocular surface, furthercomprising the local administration of pimecrolimus. In some embodimentsis a method of increasing mucin content on the ocular surface, furthercomprising the local administration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is selected from nicotine, cytisine,epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418, ABT-366833,ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101,A85380, and 5-I-A85380. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is nicotine. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is cytisine. In another embodiment of anyof the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isepibatidine. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is varenicline. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is tebanicline. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is DBO-83. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is CC4. In another embodiment of any ofthe aforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is ABT-418. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is ABT-366833. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist is ABT-202.In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is ABT-894. In another embodiment of anyof the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isSIB-1663. In another embodiment of any of the aforementioned embodimentsof increasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is GTS-21. In another embodiment of anyof the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isPHA-543613. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is PNU-282987. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is LY-2087101. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is A85380. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is selected from a compound disclosed inWO 2008/057938, WO 2009/111550, WO 2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, at least 1 microgram ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, at least5 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, at least 10 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, at least 25 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, at least 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, at least 100 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, at least250 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, at least 500 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, at least 750 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, at least 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 1 microgram and1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, between 5 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 5 micrograms and100 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, between 5 micrograms and 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 10 microgramsand 50 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, between 25 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 50 microgramsand 1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, between 100 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 100 microgramsand 750 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, between 150 micrograms and 750 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, between 150 microgramsand 600 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered once daily. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is administered at least once daily. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isadministered twice daily. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administered atleast twice daily. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered three timesdaily. In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered at least three timesdaily. In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered for one day. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is administered for at least two days. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isadministered for at least three days. In another embodiment of any ofthe aforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least four days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least five days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least seven days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least ten days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least fourteen days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least twenty one days. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredfor at least thirty days.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste,lotion, or balm. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a liquid. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a suspension. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as an aerosol. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a gel. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as an ointment. In another embodiment of any ofthe aforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a dry powder. In another embodiment of any ofthe aforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a cream. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a paste. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a lotion. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a balm.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya syringe, dropper, bottle nebulizer, atomization pump, inhaler, powderspray device, vaporizer, patch, medicated stick, pipette, or jet ofliquid. In another embodiment of any of the aforementioned embodimentsof increasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya syringe. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a dropper. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a bottle nebulizer. In another embodiment of any of theaforementioned embodiments of increasing mucin content on the ocularsurface, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by an atomization pump. In another embodiment ofany of the aforementioned embodiments of increasing mucin content on theocular surface, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by an inhaler. In another embodimentof any of the aforementioned embodiments of increasing mucin content onthe ocular surface, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a powder spray device. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a vaporizer. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a patch. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a medicated stick. Inanother embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya pipette. In another embodiment of any of the aforementionedembodiments of increasing mucin content on the ocular surface, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofincreasing mucin content on the ocular surface, the trigeminal nerve isactivated. In a further embodiment of increasing mucin content on theocular surface, the anterior ethmoidal nerve is activated. In anotherembodiment of any of the aforementioned embodiments of increasing mucincontent on the ocular surface, the nasolacrimal reflex is activated.

Increasing the Amount or Concentration of One or More Lacrimal Proteins

Provided herein, in some embodiments, is a method of increasing theamount or concentration of one or more lacrimal proteins in a subject.In some embodiments, is a method of increasing the amount orconcentration of one or more lacrimal proteins, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and does not cross the blood-brainbarrier in a pharmacologically relevant concentration. In someembodiments is method of increasing the amount or concentration of oneor more lacrimal proteins, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to atleast one of the peripheral nicotinic acetylcholine receptor subtypesselected from alpha3beta4, alpha4beta2, and alpha7. In some embodimentsis method of increasing the amount or concentration of one or morelacrimal proteins, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha3beta4. In someembodiments is method of increasing the amount or concentration of oneor more lacrimal proteins, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha4beta2. In someembodiments is method of increasing the amount or concentration of oneor more lacrimal proteins, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha7. In someembodiments is a method of increasing the amount or concentration of oneor more lacrimal proteins, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and is administered in an amount that is not systemicallybioavailable. In some embodiments is a method of increasing the amountor concentration of one or more lacrimal proteins, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist selectively binds to the peripheralnicotinic acetylcholine receptor and in an amount that does not resultin undesired psychoactive side effects. In some embodiments is a methodof increasing the amount or concentration of one or more lacrimalproteins, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor andin an amount that does not result in undesired systemic side effects. Insome embodiments is a method of increasing the amount or concentrationof one or more lacrimal proteins, wherein the lacrimal protein isepithelial growth factor, lactoferin, lacritin, prolactin,adrenocorticotropic, leucine enkephalin, ALS2CL, ARHGEF19, KIAA1109,PLXNA1, POLG, WIPI1, ZMIZ2 or other proteins of the tear proteome. Insome embodiments is a method of increasing the amount or concentrationof one or more lacrimal proteins, wherein at least one lacrimal proteinis epithelial growth factor. In some embodiments is a method ofincreasing the amount or concentration of one or more lacrimal proteins,wherein at least one lacrimal protein is lactoferin. In some embodimentsis a method of increasing the amount or concentration of one or morelacrimal proteins, wherein at least one lacrimal protein is lacritin. Insome embodiments is a method of increasing the amount or concentrationof one or more lacrimal proteins, wherein at least one lacrimal proteinis prolactin. In some embodiments is a method of increasing the amountor concentration of one or more lacrimal proteins, wherein at least onelacrimal protein is adrenocorticotropic. In some embodiments is a methodof increasing the amount or concentration of one or more lacrimalproteins, wherein at least one lacrimal protein is leucine enkephalin.In some embodiments is a method of increasing the amount orconcentration of one or more lacrimal proteins, wherein at least onelacrimal protein is ALS2CL. In some embodiments is a method ofincreasing the amount or concentration of one or more lacrimal proteins,wherein at least one lacrimal protein is ARHGEF19. In some embodimentsis a method of increasing the amount or concentration of one or morelacrimal proteins, wherein at least one lacrimal protein is KIAA1109. Insome embodiments is a method of increasing the amount or concentrationof one or more lacrimal proteins, wherein at least one lacrimal proteinis PLXNA1. In some embodiments is a method of increasing the amount orconcentration of one or more lacrimal proteins, wherein at least onelacrimal protein is POLG. In some embodiments is a method of increasingthe amount or concentration of one or more lacrimal proteins, wherein atleast one lacrimal protein is WIPI1. In some embodiments is a method ofincreasing the amount or concentration of one or more lacrimal proteins,wherein at least one lacrimal protein is ZMIZ2. In some embodiments is amethod of increasing the amount or concentration of one or more lacrimalproteins, further comprising the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. In some embodimentsis a method of increasing the amount or concentration of one or morelacrimal proteins, further comprising the local administration of one ormore substances that prevent the entry or reduce the entry of thenicotinic acetylcholine receptor into the desensitized state, orfacilitate the recovery of the nicotinic acetylcholine receptor from thedesensitized state. In some embodiments is a method of increasing theamount or concentration of one or more lacrimal proteins, furthercomprising the local administration of one or more substances thatprevent or facilitate the recovery of the nicotinic acetylcholinereceptor from the desensitized state selected from protein kinase C(PKC) or factors that upregulate or up-modulate PKC, cAMP-dependentprotein kinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments is a method of increasingthe amount or concentration of one or more lacrimal proteins, furthercomprising the local administration of one or more substances thatprevent the entry or reduce the entry of the nicotinic acetylcholinereceptor into the desensitized state, or facilitate the recovery of thenicotinic acetylcholine receptor from the desensitized state selectedfrom protein kinase C (PKC) or factors that upregulate or up-modulatePKC, cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of increasing the amount or concentration of one or more lacrimalproteins, further comprising the local administration of protein kinaseC (PKC) or factors that upregulate or up-modulate PKC. In someembodiments is a method of increasing the amount or concentration of oneor more lacrimal proteins, further comprising the local administrationof cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA. In some embodiments is a method of increasing theamount or concentration of one or more lacrimal proteins, furthercomprising the local administration of a calcineurin inhibitor. In someembodiments is a method of increasing the amount or concentration of oneor more lacrimal proteins, further comprising the local administrationof a calcineurin inhibitor, wherein the calcineurin inhibitor isselected from cyclosporine, pimecrolimus, and tacrolimus. In someembodiments is a method of increasing the amount or concentration of oneor more lacrimal proteins, further comprising the local administrationof cyclosporine. In some embodiments is a method of increasing theamount or concentration of one or more lacrimal proteins, furthercomprising the local administration of pimecrolimus. In some embodimentsis a method of increasing the amount or concentration of one or morelacrimal proteins, further comprising the local administration oftacrolimus.

In a further embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is selected from nicotine,cytisine, epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418,ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987,LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is nicotine. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist iscytisine. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, the nicotinic acetylcholine receptor agonist is epibatidine.In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is varenicline. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is tebanicline. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is DBO-83. In another embodiment of anyof the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is CC4. In another embodiment of any ofthe aforementioned embodiments of increasing the amount or concentrationof one or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is ABT-418. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isABT-366833. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isABT-202. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, the nicotinic acetylcholine receptor agonist is ABT-894. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is SIB-1663. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is GTS-21. In another embodiment of anyof the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is PHA-543613. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is PNU-282987. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is LY-2087101. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is A85380. In another embodiment of anyof the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is selected from a compounddisclosed in WO 2008/057938, WO 2009/111550, WO 2010/028011, or WO2010/028033.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,at least 1 microgram of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, at least 5 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,at least 10 micrograms of the nicotinic acetylcholine receptor agonistis administered into the nasal cavity. In another embodiment of any ofthe aforementioned embodiments of increasing the amount or concentrationof one or more lacrimal proteins, at least 25 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, at least 50 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, at least 100 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, at least 250 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,at least 500 micrograms of the nicotinic acetylcholine receptor agonistis administered into the nasal cavity. In another embodiment of any ofthe aforementioned embodiments of increasing the amount or concentrationof one or more lacrimal proteins, at least 750 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, at least 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, between 1microgram and 1000 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, between 5 micrograms and1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, between 5 micrograms and 100 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, between 5 micrograms and 50 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, between 10 micrograms and 50 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,between 25 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, between 50micrograms and 1000 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, between 100 microgramsand 1000 micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, between 100 micrograms and 750 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, between 150 micrograms and 750 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, between 150 micrograms and 600 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered once daily.In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered at leastonce daily. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered twice daily. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered at least twice daily. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered three times daily. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered at leastthree times daily. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered for one day. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered for at least two days. In another embodiment ofany of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered for at least three days.In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered for atleast four days. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered for at least five days. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered for at least seven days. In another embodimentof any of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered for at least ten days. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered for atleast fourteen days. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered for at least twenty one days. In another embodiment of anyof the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered inalternating nostrils.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a liquid, suspension, aerosol, gel, ointment, drypowder, cream, paste, lotion, or balm. In another embodiment of any ofthe aforementioned embodiments of increasing the amount or concentrationof one or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a liquid. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa suspension. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as an aerosol. In another embodimentof any of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa gel. In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as an ointment. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a dry powder. Inanother embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a cream. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a paste. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa lotion. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a balm.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a syringe, dropper, bottle nebulizer, atomization pump,inhaler, powder spray device, vaporizer, patch, medicated stick,pipette, or jet of liquid. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a syringe. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya dropper. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a bottle nebulizer. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity byan atomization pump. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by an inhaler. In another embodimentof any of the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya powder spray device. In another embodiment of any of theaforementioned embodiments of increasing the amount or concentration ofone or more lacrimal proteins, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a vaporizer. In anotherembodiment of any of the aforementioned embodiments of increasing theamount or concentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya patch. In another embodiment of any of the aforementioned embodimentsof increasing the amount or concentration of one or more lacrimalproteins, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a medicated stick. In another embodiment of anyof the aforementioned embodiments of increasing the amount orconcentration of one or more lacrimal proteins, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya pipette. In another embodiment of any of the aforementionedembodiments of increasing the amount or concentration of one or morelacrimal proteins, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofincreasing the amount or concentration of one or more lacrimal proteins,the trigeminal nerve is activated. In a further embodiment of increasingthe amount or concentration of one or more lacrimal proteins, theanterior ethmoidal nerve is activated. In another embodiment of any ofthe aforementioned embodiments of increasing the amount or concentrationof one or more lacrimal proteins, the nasolacrimal reflex is activated.

Enhancing Tear Clearance

Provided herein, in some embodiments, is a method of enhancing tearclearance in a subject. In some embodiments, is a method of enhancingtear clearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonistselectively binds to the peripheral nicotinic acetylcholine receptor anddoes not cross the blood-brain barrier in a pharmacologically relevantconcentration. In some embodiments is method of enhancing tearclearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to at least one of the peripheralnicotinic acetylcholine receptor subtypes selected from alpha3beta4,alpha4beta2, and alpha7. In some embodiments is method of enhancing tearclearance, comprising the local administration of a therapeuticallyeffective amount of a nicotinic acetylcholine receptor agonist into thenasal cavity of an individual in need thereof, wherein the agonist doesnot cross the blood-brain barrier in a pharmacologically relevantconcentration and selectively binds to the peripheral nicotinicacetylcholine receptor subtype alpha3beta4. In some embodiments ismethod of enhancing tear clearance, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist does not cross the blood-brain barrier in apharmacologically relevant concentration and selectively binds to theperipheral nicotinic acetylcholine receptor subtype alpha4beta2. In someembodiments is method of enhancing tear clearance, comprising the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the agonist does not cross the blood-brain barrierin a pharmacologically relevant concentration and selectively binds tothe peripheral nicotinic acetylcholine receptor subtype alpha7. In someembodiments is a method of enhancing tear clearance, comprising thelocal administration of a therapeutically effective amount of anicotinic acetylcholine receptor agonist into the nasal cavity of anindividual in need thereof, wherein the agonist selectively binds to theperipheral nicotinic acetylcholine receptor and is administered in anamount that is not systemically bioavailable. In some embodiments is amethod of enhancing tear clearance, comprising the local administrationof a therapeutically effective amount of a nicotinic acetylcholinereceptor agonist into the nasal cavity of an individual in need thereof,wherein the agonist selectively binds to the peripheral nicotinicacetylcholine receptor and in an amount that does not result inundesired psychoactive side effects. In some embodiments is a method ofenhancing tear clearance, comprising the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof, whereinthe agonist selectively binds to the peripheral nicotinic acetylcholinereceptor and in an amount that does not result in undesired systemicside effects. In some embodiments is a method of enhancing tearclearance, further comprising the local administration of one or moresubstances that prevent or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. In some embodimentsis a method of enhancing tear clearance, further comprising the localadministration of one or more substances that prevent the entry orreduce the entry of the nicotinic acetylcholine receptor into thedesensitized state, or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state. In some embodimentsis a method of enhancing tear clearance, further comprising the localadministration of one or more substances that prevent or facilitate therecovery of the nicotinic acetylcholine receptor from the desensitizedstate selected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. In someembodiments is a method of enhancing tear clearance, further comprisingthe local administration of one or more substances that prevent theentry or reduce the entry of the nicotinic acetylcholine receptor intothe desensitized state, or facilitate the recovery of the nicotinicacetylcholine receptor from the desensitized state selected from proteinkinase C (PKC) or factors that upregulate or up-modulate PKC,cAMP-dependent protein kinase (PKA) or factors that upregulate orup-modulate PKA, and calcineurin inhibitors. In some embodiments is amethod of enhancing tear clearance, further comprising the localadministration of protein kinase C (PKC) or factors that upregulate orup-modulate PKC. In some embodiments is a method of enhancing tearclearance, further comprising the local administration of cAMP-dependentprotein kinase (PKA) or factors that upregulate or up-modulate PKA. Insome embodiments is a method of enhancing tear clearance, furthercomprising the local administration of a calcineurin inhibitor. In someembodiments is a method of enhancing tear clearance, further comprisingthe local administration of a calcineurin inhibitor, wherein thecalcineurin inhibitor is selected from cyclosporine, pimecrolimus, andtacrolimus. In some embodiments is a method of enhancing tear clearance,further comprising the local administration of cyclosporine. In someembodiments is a method of enhancing tear clearance, further comprisingthe local administration of pimecrolimus. In some embodiments is amethod of enhancing tear clearance, further comprising the localadministration of tacrolimus.

In a further embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is nicotine. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is cytisine. In another embodiment of anyof the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is epibatidine. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is varenicline.In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis tebanicline. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is DBO-83. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is CC4. In another embodiment of any ofthe aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is ABT-418. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is ABT-366833.In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis ABT-202. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is ABT-894. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is SIB-1663. In another embodiment of anyof the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is GTS-21. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis PNU-282987. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is LY-2087101. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is A85380. In another embodiment of anyof the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is 5-I-A85380.

In a further embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis selected from a compound disclosed in WO 2008/057938, WO 2009/111550,WO 2010/028011, or WO 2010/028033.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, at least 1 microgram of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, at least 5 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 10 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 25 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 50 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 100 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 250 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 500 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 750 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, at least 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, between 1 microgram and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, between 5 micrograms and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof enhancing tear clearance, between 5 micrograms and 100 micrograms ofthe nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, between 5 micrograms and 50micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, between 10micrograms and 50 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity. In another embodiment ofany of the aforementioned embodiments of enhancing tear clearance,between 25 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, between 50 micrograms and 1000 micrograms of the nicotinicacetylcholine receptor agonist is administered into the nasal cavity. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, between 100 micrograms and 1000 micrograms of thenicotinic acetylcholine receptor agonist is administered into the nasalcavity. In another embodiment of any of the aforementioned embodimentsof enhancing tear clearance, between 100 micrograms and 750 microgramsof the nicotinic acetylcholine receptor agonist is administered into thenasal cavity. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, between 150 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, between 150micrograms and 600 micrograms of the nicotinic acetylcholine receptoragonist is administered into the nasal cavity.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered once daily. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered at least once daily. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered twice daily. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered at least twice daily. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered three times daily. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered at least three timesdaily. In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered for one day. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered for at least two days. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered for at least three days. In another embodiment of any ofthe aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is administered for at leastfour days. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered for at least five days. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is administeredfor at least seven days. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered for at least ten days. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered for at least fourteen days. In another embodiment of any ofthe aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is administered for at leasttwenty one days. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered for at least thirty days.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered in alternating nostrils.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity as a liquid, suspension, aerosol,gel, ointment, dry powder, cream, paste, lotion, or balm. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a liquid. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa suspension. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as an aerosol. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a gel. In another embodiment ofany of the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as an ointment. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa dry powder. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a cream. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a paste. In another embodiment ofany of the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a lotion. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a balm.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by a syringe, dropper, bottlenebulizer, atomization pump, inhaler, powder spray device, vaporizer,patch, medicated stick, pipette, or jet of liquid. In another embodimentof any of the aforementioned embodiments of enhancing tear clearance,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a syringe. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya dropper. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by a bottlenebulizer. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by an atomizationpump. In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the nicotinic acetylcholine receptor agonistis administered into the nasal cavity by an inhaler. In anotherembodiment of any of the aforementioned embodiments of enhancing tearclearance, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity by a powder spray device. In another embodiment ofany of the aforementioned embodiments of enhancing tear clearance, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a vaporizer. In another embodiment of any of theaforementioned embodiments of enhancing tear clearance, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya patch. In another embodiment of any of the aforementioned embodimentsof enhancing tear clearance, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a medicated stick. Inanother embodiment of any of the aforementioned embodiments of enhancingtear clearance, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a pipette. In another embodimentof any of the aforementioned embodiments of enhancing tear clearance,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a jet of liquid.

In another embodiment of any of the aforementioned embodiments ofenhancing tear clearance, the trigeminal nerve is activated. In afurther embodiment of enhancing tear clearance, the anterior ethmoidalnerve is activated. In another embodiment of any of the aforementionedembodiments of enhancing tear clearance, the nasolacrimal reflex isactivated.

Certain Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” or “and” means “and/or” unless statedotherwise. Furthermore, use of the term “including” as well as otherforms, such as “include”, “includes,” and “included,” is not limiting.The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thepharmaceutical formulation comprising a nicotinic acetylcholine receptoragonist as disclosed herein required to provide a clinically significantdecrease in disease symptoms. An appropriate “effective” amount in anyindividual case may be determined using techniques, such as a doseescalation study.

The terms “individual”, “subject”, and “patient” encompass mammals andnon-mammals. Examples of mammals include, but are not limited to, anymember of the Mammalian class: humans, non-human primates such aschimpanzees, and other apes and monkey species; farm animals such ascattle, horses, sheep, goats, swine; domestic animals such as rabbits,dogs, and cats; laboratory animals including rodents, such as rats, miceand guinea pigs, and the like. In one embodiment, the mammal is a human.

A “tissue” comprises two or more cells. The two or more cells may have asimilar function and/or function. The tissue may be a connective tissue,epithelial tissue, muscular tissue, or nervous tissue. Alternatively,the tissue is a bone, tendon (both referred to as musculoskeletalgrafts), cornea, skin, heart valve, or vein.

An “organ” comprises two or more tissues. The two or more tissues mayperform a specific function or group of functions. In some instances,the organ is a lung, mouth, nose, parathyroid gland, pineal gland,pituitary gland, carotid body, salivary gland, skin, gall bladder,pancreas, small intestine, stomach, spleen, spinal cord, thymus, thyroidgland, trachea, uterus, or vermiform appendix. Alternatively, the organis an adrenal gland, appendix, brain, bladder, kidney, intestine, largeintestine, small intestine, liver, heart, or muscle.

The term “nicotinic acetylcholine receptor agonist” encompasses a fullagonist or a partial agonist of the nicotinic acetylcholine receptor.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, preventing progression ofthe condition, inhibiting the disease or condition, e.g., arresting thedevelopment of the disease or condition, relieving the disease orcondition, causing regression of the disease or condition, relieving acondition caused by the disease or condition, or stopping the symptomsof the disease or condition. In one embodiment, treatment isprophylactic treatment. In another embodiment, treatment refers totherapeutic treatment.

The term “does not cross the blood-brain barrier in a pharmacologicallyrelevant concentration” as used herein, refers to an insufficient amountof a nicotinic acetylcholine receptor agonist as disclosed hereinpassing through the blood-brain barrier to produce a pharmacologicalresponse.

The term “undesired psychoactive side effects” as used herein, refers tounintended effects in the brain including, but not limited to, anxiety,depression, hallucination, euphoria, addiction, sleepdisorder/disturbances, insomnia, abnormal dreams, and nightmares.

The term “undesired systemic side effects” as used herein, refers tounintended effects in the body including, but not limited to, abdominalpain, vomiting, nausea, constipation, diarrhea, flatulence, dyspepsia,and dry mouth.

The term “nicotinic acetylcholine receptor agonist formulated to preventdesensitization” as used herein, refers to a formulation that does notresult in tolerance, dependence, withdrawal, or loss of sensitivity tothe effect of the nicotinic acetylcholine receptor agonist.

The term “environmentally challenging conditions” as used herein, refersto external conditions including naturally and man-made conditions.Naturally occurring environmentally challenging conditions include, butare not limited to, exposure to smoke, wind, and dry climates. Man-madeenvironmentally challenging conditions include, but are not limited to,exposure to pollution from automobiles, factories, and airplanes, aswell as homes/offices with low humidity, high airflow or poor airquality. In some embodiments, “environmentally challenging conditions”refer to controlled challenge environments commonly used for dry eyeclinical trials.

The term “ocular discomfort” includes, but is not limited to, thesymptoms of dry eye disease, such as itchiness, dryness, photophobia,blurriness, pain, sticky feeling, burning, stinging, and foreign bodysensation. In some embodiments, ocular discomfort is associated withblepharitis, meibomian gland dysfunction, allergic conjunctivitis,ocular surface toxicity and irritation, lacrimal drainage problems, oreyelid disorders.

The term “soft drug” as used herein, refers to a drug substance that israpidly metabolized into an inactive form immediately after achievingthe therapeutic effect.

Nicotinic Acetylcholine Receptor Agonists

The methods described herein comprise the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is a full agonist. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist is apartial agonist. In some embodiments of the methods described herein,the nicotinic acetylcholine receptor agonist is selected from nicotine,cytisine, epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418,ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987,LY-2087101, A85380, and 5-I-A85380. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isnicotine. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is cytisine. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is epibatidine. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isvarenicline. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is tebanicline. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is DBO-83. In some embodiments of the methods describedherein, the nicotinic acetylcholine receptor agonist is CC4. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is ABT-418. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isABT-366833. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is ABT-202. In some embodimentsof the methods described herein, the nicotinic acetylcholine receptoragonist is ABT-894. In some embodiments of the methods described herein,the nicotinic acetylcholine receptor agonist is SIB-1663. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is GTS-21. In some embodiments of the methods describedherein, the nicotinic acetylcholine receptor agonist is PHA-543613. Insome embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is PNU-282987. In some embodiments of themethods described herein, the nicotinic acetylcholine receptor agonistis LY-2087101. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is A85380. In some embodimentsof the methods described herein, the nicotinic acetylcholine receptoragonist is 5-I-A85380. In some embodiments of the methods describedherein, the nicotinic acetylcholine receptor agonist is selected from acompound disclosed in WO 2008/057938, WO 2009/111550, WO 2010/028011, orWO 2010/028033.

In some embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is a soft drug.

In some embodiments of the methods described herein is a nicotinicacetylcholine receptor agonist having the structure:

or a pharmaceutically acceptable salt thereof.

Intranasal Route of Administration

The methods described herein comprise the local administration of atherapeutically effective amount of a nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need thereof. In someembodiments, the methods described herein comprise the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as a liquid, suspension, aerosol,gel, ointment, dry powder, cream, paste, lotion, or balm. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a liquid. Insome embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa suspension. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as an aerosol. In some embodiments of the methods describedherein, the nicotinic acetylcholine receptor agonist is administeredinto the nasal cavity as a gel. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity as an ointment. In some embodimentsof the methods described herein, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity as a dry powder. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity as a cream. Insome embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity asa paste. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity as a lotion. In some embodiments of the methods described herein,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity as a balm.

In some embodiments, the methods described herein comprise the localadministration of a therapeutically effective amount of a nicotinicacetylcholine receptor agonist into the nasal cavity of an individual inneed thereof, wherein the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a syringe, dropper, bottlenebulizer, atomization pump, inhaler, powder spray device, vaporizer,patch, medicated stick, pipette, or jet of liquid. In some embodimentsof the methods described herein, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a syringe. In someembodiments of the methods described herein, the nicotinic acetylcholinereceptor agonist is administered into the nasal cavity by a dropper. Insome embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya bottle nebulizer. In some embodiments of the methods described herein,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by an atomization pump. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by an inhaler. In some embodiments ofthe methods described herein, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a powder spray device.In some embodiments of the methods described herein, the nicotinicacetylcholine receptor agonist is administered into the nasal cavity bya vaporizer. In some embodiments of the methods described herein, thenicotinic acetylcholine receptor agonist is administered into the nasalcavity by a patch. In some embodiments of the methods described herein,the nicotinic acetylcholine receptor agonist is administered into thenasal cavity by a medicated stick. In some embodiments of the methodsdescribed herein, the nicotinic acetylcholine receptor agonist isadministered into the nasal cavity by a pipette. In some embodiments ofthe methods described herein, the nicotinic acetylcholine receptoragonist is administered into the nasal cavity by a jet of liquid.

Pharmaceutical Formulations, Methods of Dosing, and Treatment Regimens

Also provided herein are pharmaceutical formulations of nicotinicacetylcholine receptor agonists for local administration into the nasalcavity of an individual. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that is notsystemically bioavailable. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that is notsystemically bioavailable, further comprising one or more substancesselected from protein kinase C (PKC) or factors that upregulate orup-modulate PKC, cAMP-dependent protein kinase (PKA) or factors thatupregulate or up-modulate PKA, and calcineurin inhibitors. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, furthercomprising protein kinase C (PKC) or factors that upregulate orup-modulate PKC. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, further comprising cAMP-dependent protein kinase (PKA) orfactors that upregulate or up-modulate PKA. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, further comprising a calcineurininhibitor. In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, further comprising a calcineurin inhibitor, wherein thecalcineurin inhibitor is selected from cyclosporine, pimecrolimus, andtacrolimus. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, further comprising a calcineurin inhibitor, wherein thecalcineurin inhibitor is cyclosporine. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, further comprising a calcineurininhibitor, wherein the calcineurin inhibitor is pimecrolimus. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, furthercomprising a calcineurin inhibitor, wherein the calcineurin inhibitor istacrolimus.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonist isselected from nicotine, cytisine, epibatidine, varenicline, tebanicline,DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21,PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is nicotine. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is cytisine. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is epibatidine. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is varenicline. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is tebanicline. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that is not systemically bioavailable, wherein thenicotinic acetylcholine receptor agonist is DBO-83. In some embodimentsis a pharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is CC4. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is ABT-418. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is ABT-366833. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is ABT-202. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is ABT-894. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is SIB-1663. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is GTS-21. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is PHA-543613. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is PNU-282987. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is LY-2087101. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is A85380. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat is not systemically bioavailable, wherein the nicotinicacetylcholine receptor agonist is 5-I-A85380.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonist isselected from a compound disclosed in WO 2008/057938, WO 2009/111550, WO2010/028011, or WO 2010/028033.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonistselectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonistselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha3beta4. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonistselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha4beta2. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonistselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha7.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonist is asoft drug.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that is not systemicallybioavailable, wherein the nicotinic acetylcholine receptor agonist has astructure selected from:

or a pharmaceutically acceptable salt thereof.

Further described herein, in some embodiments, is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects. In some embodimentsis a pharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, furthercomprising one or more substances selected from protein kinase C (PKC)or factors that upregulate or up-modulate PKC, cAMP-dependent proteinkinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, further comprisingprotein kinase C (PKC) or factors that upregulate or up-modulate PKC. Insome embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, further comprising cAMP-dependent proteinkinase (PKA) or factors that upregulate or up-modulate PKA. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, further comprising a calcineurin inhibitor. In some embodimentsis a pharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, furthercomprising a calcineurin inhibitor, wherein the calcineurin inhibitor isselected from cyclosporine, pimecrolimus, and tacrolimus. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, further comprising a calcineurin inhibitor, wherein thecalcineurin inhibitor is cyclosporine. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, furthercomprising a calcineurin inhibitor, wherein the calcineurin inhibitor ispimecrolimus. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, further comprising a calcineurin inhibitor,wherein the calcineurin inhibitor is tacrolimus.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is nicotine. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired psychoactive side effects, wherein the nicotinic acetylcholinereceptor agonist is cytisine. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, wherein the nicotinicacetylcholine receptor agonist is epibatidine. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, wherein thenicotinic acetylcholine receptor agonist is varenicline. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, wherein the nicotinic acetylcholine receptor agonist istebanicline. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is DBO-83. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired psychoactive side effects, wherein the nicotinic acetylcholinereceptor agonist is CC4. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, wherein the nicotinicacetylcholine receptor agonist is ABT-418. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, wherein thenicotinic acetylcholine receptor agonist is ABT-366833. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, wherein the nicotinic acetylcholine receptor agonist isABT-202. In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is ABT-894. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired psychoactive side effects, wherein the nicotinic acetylcholinereceptor agonist is SIB-1663. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, wherein the nicotinicacetylcholine receptor agonist is GTS-21. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, wherein thenicotinic acetylcholine receptor agonist is PHA-543613. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, wherein the nicotinic acetylcholine receptor agonist isPNU-282987. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is LY-2087101. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, wherein the nicotinicacetylcholine receptor agonist is A85380. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired psychoactive side effects, wherein thenicotinic acetylcholine receptor agonist is 5-I-A85380.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is selected from a compound disclosed in WO 2008/057938, WO2009/111550, WO 2010/028011, or WO 2010/028033.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist is a soft drug.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist has a structure selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist selectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredpsychoactive side effects, wherein the nicotinic acetylcholine receptoragonist selectively binds to the peripheral nicotinic acetylcholinereceptor subtype alpha3beta4. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired psychoactive side effects, wherein the nicotinicacetylcholine receptor agonist selectively binds to the peripheralnicotinic acetylcholine receptor subtype alpha4beta2. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired psychoactive sideeffects, wherein the nicotinic acetylcholine receptor agonistselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha7.

Further described herein, in some embodiments, is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, furthercomprising one or more substances selected from protein kinase C (PKC)or factors that upregulate or up-modulate PKC, cAMP-dependent proteinkinase (PKA) or factors that upregulate or up-modulate PKA, andcalcineurin inhibitors. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, further comprisingprotein kinase C (PKC) or factors that upregulate or up-modulate PKC. Insome embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, further comprising cAMP-dependent protein kinase(PKA) or factors that upregulate or up-modulate PKA. In some embodimentsis a pharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, furthercomprising a calcineurin inhibitor. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, furthercomprising a calcineurin inhibitor, wherein the calcineurin inhibitor isselected from cyclosporine, pimecrolimus, and tacrolimus. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired systemic sideeffects, further comprising a calcineurin inhibitor, wherein thecalcineurin inhibitor is cyclosporine. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, furthercomprising a calcineurin inhibitor, wherein the calcineurin inhibitor ispimecrolimus. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, further comprising a calcineurin inhibitor,wherein the calcineurin inhibitor is tacrolimus.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is selected from nicotine, cytisine, epibatidine, varenicline,tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894,SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and5-I-A85380. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is nicotine. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired systemic side effects, wherein the nicotinic acetylcholinereceptor agonist is cytisine. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, wherein the nicotinicacetylcholine receptor agonist is epibatidine. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, wherein thenicotinic acetylcholine receptor agonist is varenicline. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired systemic sideeffects, wherein the nicotinic acetylcholine receptor agonist istebanicline. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is DBO-83. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired systemic side effects, wherein the nicotinic acetylcholinereceptor agonist is CC4. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, wherein the nicotinicacetylcholine receptor agonist is ABT-418. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, wherein thenicotinic acetylcholine receptor agonist is ABT-366833. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired systemic sideeffects, wherein the nicotinic acetylcholine receptor agonist isABT-202. In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is ABT-894. In some embodiments is a pharmaceutical formulationfor local administration into the nasal cavity of an individualcomprising a nicotinic acetylcholine receptor agonist formulated toprevent desensitization and in a dosage amount that does not result inundesired systemic side effects, wherein the nicotinic acetylcholinereceptor agonist is SIB-1663. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, wherein the nicotinicacetylcholine receptor agonist is GTS-21. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, wherein thenicotinic acetylcholine receptor agonist is PHA-543613. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired systemic sideeffects, wherein the nicotinic acetylcholine receptor agonist isPNU-282987. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is LY-2087101. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, wherein the nicotinicacetylcholine receptor agonist is A85380. In some embodiments is apharmaceutical formulation for local administration into the nasalcavity of an individual comprising a nicotinic acetylcholine receptoragonist formulated to prevent desensitization and in a dosage amountthat does not result in undesired systemic side effects, wherein thenicotinic acetylcholine receptor agonist is 5-I-A85380.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is selected from a compound disclosed in WO 2008/057938, WO2009/111550, WO 2010/028011, or WO 2010/028033.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist is a soft drug.

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist has a structure selected from:

or a pharmaceutically acceptable salt thereof

In some embodiments is a pharmaceutical formulation for localadministration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist selectively binds to at least one of the peripheral nicotinicacetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2,and alpha7. In some embodiments is a pharmaceutical formulation forlocal administration into the nasal cavity of an individual comprising anicotinic acetylcholine receptor agonist formulated to preventdesensitization and in a dosage amount that does not result in undesiredsystemic side effects, wherein the nicotinic acetylcholine receptoragonist selectively binds to the peripheral nicotinic acetylcholinereceptor subtype alpha3beta4. In some embodiments is a pharmaceuticalformulation for local administration into the nasal cavity of anindividual comprising a nicotinic acetylcholine receptor agonistformulated to prevent desensitization and in a dosage amount that doesnot result in undesired systemic side effects, wherein the nicotinicacetylcholine receptor agonist selectively binds to the peripheralnicotinic acetylcholine receptor subtype alpha4beta2. In someembodiments is a pharmaceutical formulation for local administrationinto the nasal cavity of an individual comprising a nicotinicacetylcholine receptor agonist formulated to prevent desensitization andin a dosage amount that does not result in undesired systemic sideeffects, wherein the nicotinic acetylcholine receptor agonistselectively binds to the peripheral nicotinic acetylcholine receptorsubtype alpha7.

In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises about0.1 mg/mL of the nicotinic acetylcholine receptor agonist. In anotherembodiment of any of the aforementioned pharmaceutical formulationembodiments, the pharmaceutical formulation comprises about 0.2 mg/mL ofthe nicotinic acetylcholine receptor agonist. In another embodiment ofany of the aforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 0.5 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 1 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 2 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 3 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 4 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 5 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 6 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 7 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 8 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 9 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 10 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 12 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 15 mg/mL of the nicotinicacetylcholine receptor agonist. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises about 20 mg/mL of the nicotinicacetylcholine receptor agonist.

In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 1 microgram of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 5 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 10 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 25 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 50 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 100 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 250 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 500 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 750 micrograms of the nicotinic acetylcholine receptor agonist perdose. In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprises atleast 1000 micrograms of the nicotinic acetylcholine receptor agonistper dose. In another embodiment of any of the aforementionedpharmaceutical formulation embodiments, the pharmaceutical formulationcomprises between 1 microgram and 1000 micrograms of the nicotinicacetylcholine receptor agonist per dose. In another embodiment of any ofthe aforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises between 5 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist per dose. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprisesbetween 5 micrograms and 100 micrograms of the nicotinic acetylcholinereceptor agonist per dose. In another embodiment of any of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises between 5 micrograms and 50micrograms of the nicotinic acetylcholine receptor agonist per dose. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprisesbetween 10 micrograms and 50 micrograms of the nicotinic acetylcholinereceptor agonist per dose. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises between 25 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist per dose. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprisesbetween 50 micrograms and 1000 micrograms of the nicotinic acetylcholinereceptor agonist per dose. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises between 100 micrograms and 1000micrograms of the nicotinic acetylcholine receptor agonist is per dose.In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprisesbetween 100 micrograms and 750 micrograms of the nicotinic acetylcholinereceptor agonist per dose. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation comprises between 150 micrograms and 750micrograms of the nicotinic acetylcholine receptor agonist per dose. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation comprisesbetween 150 micrograms and 600 micrograms of the nicotinic acetylcholinereceptor agonist per dose.

In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredonce daily. In another embodiment of any of the aforementionedpharmaceutical formulation embodiments, the pharmaceutical formulationis administered at least once daily. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered twice daily. In anotherembodiment of any of the aforementioned pharmaceutical formulationembodiments, the pharmaceutical formulation is administered at leasttwice daily. In another embodiment of any of the aforementionedpharmaceutical formulation embodiments, the pharmaceutical formulationis administered three times daily. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered at least three times daily.In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredfor one day. In another embodiment of any of the aforementionedpharmaceutical formulation embodiments, the pharmaceutical formulationis administered for at least two days. In another embodiment of any ofthe aforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered for at least three days. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredfor at least four days. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered for at least five days. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredfor at least seven days. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered for at least ten days. Inanother embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredfor at least fourteen days. In another embodiment of any of theaforementioned pharmaceutical formulation embodiments, thepharmaceutical formulation is administered for at least twenty one days.In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredfor at least thirty days.

In another embodiment of any of the aforementioned pharmaceuticalformulation embodiments, the pharmaceutical formulation is administeredin alternating nostrils.

In certain embodiments, the pharmaceutical formulations described hereinare administered for prophylactic and/or therapeutic treatments. Incertain therapeutic applications, the pharmaceutical formulations areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation clinical trial.

In prophylactic applications, the pharmaceutical formulations describedherein are administered to a patient susceptible to or otherwise at riskof a particular disease, disorder or condition. Such an amount isdefined to be a “prophylactically effective amount or dose.” In thisuse, the precise amounts also depend on the patient's state of health,weight, and the like. When used in a patient, effective amounts for thisuse will depend on the severity and course of the disease, disorder orcondition, previous therapy, the patient's health status and response tothe drugs, and the judgment of the treating physician.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the pharmaceuticalformulations are administered chronically, that is, for an extendedperiod of time, including throughout the duration of the patient's lifein order to ameliorate or otherwise control or limit the symptoms of thepatient's disease or condition.

In certain embodiments wherein a patient's status does improve, the doseof the pharmaceutical formulation being administered may be temporarilyreduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). In specific embodiments, the length of the drug holidayis between 2 days and 1 year, including by way of example only, 2 days,3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, or more than 28 days. The dose reduction during a drugholiday is, by way of example only, by 10%-100%, including by way ofexample only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, and 100%.

In certain embodiments the dose of the pharmaceutical formulation beingadministered may be temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug diversion”). In specificembodiments, the length of the drug diversion is between 2 days and 1year, including by way of example only, 2 days, 3 days, 4 days, 5 days,6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or morethan 28 days. The dose reduction during a drug diversion is, by way ofexample only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%. After a suitable length of time, the normal dosingschedule is optionally reinstated.

In some embodiments, once improvement of the patient's conditions hasoccurred, a maintenance dose is administered if necessary. Subsequently,in specific embodiments, the dosage or the frequency of administration,or both, is reduced, as a function of the symptoms, to a level at whichthe improved disease, disorder or condition is retained. In certainembodiments, however, the patient requires intermittent treatment on along-term basis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular pharmaceuticalformulation, disease condition and its severity, the identity (e.g.,weight, sex) of the subject or host in need of treatment, but cannevertheless be determined according to the particular circumstancessurrounding the case, including, e.g., the specific nicotinicacetylcholine receptor agonist being administered, the condition beingtreated, and the subject being treated.

A pharmaceutical formulation, as used herein, refers to a mixture of anicotinic acetylcholine receptor agonist as described herein with otherchemical components (i.e. pharmaceutically acceptable inactiveingredients), such as carriers, excipients, binders, filling agents,suspending agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombination thereof. In some embodiments, the pharmaceuticalformulations described herein are mixed with other active ingredients,as in combination therapy. In some embodiments, the pharmaceuticalformulations include other therapeutically valuable substances. In otherembodiments, the pharmaceutical formulations include other medicinal orpharmaceutical agents, carriers, adjuvants, preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure, and/or buffers.

In some embodiments, the pharmaceutical formulations described hereinrefer to a mixture of a nicotinic acetylcholine receptor agonist and abuffer. In some embodiments, the pharmaceutical formulations describedherein refer to a mixture of a nicotinic acetylcholine receptor agonistand a phosphate buffer. In some embodiments, the pharmaceuticalformulations described herein refer to a mixture of a nicotinicacetylcholine receptor agonist and a phosphate buffer, wherein the pH ofthe phosphate buffer is around 7.0. In some embodiments, thepharmaceutical formulations described herein refer to a mixture of anicotinic acetylcholine receptor agonist and a phosphate-citrate buffer.In some embodiments, the pharmaceutical formulations described hereinrefer to a mixture of a nicotinic acetylcholine receptor agonist and aphosphate-citrate buffer, wherein the pH of the phosphate-citrate bufferis around 6.0. In some embodiments, the pharmaceutical formulationsdescribed herein refer to a mixture of a nicotinic acetylcholinereceptor agonist and a phosphate-citrate buffer. In some embodiments,the pharmaceutical formulations described herein refer to a mixture of anicotinic acetylcholine receptor agonist and a phosphate-citrate buffer,wherein the pH of the phosphate-citrate buffer is around 5.0.

The pharmaceutical formulation facilitates administration of thecompound to an organism. In practicing the methods provided herein,therapeutically effective amounts of nicotinic acetylcholine receptoragonist described herein are administered in a pharmaceuticalformulation to a mammal having a disease, disorder, or condition to betreated. In some embodiments, the mammal is a human. A therapeuticallyeffective amount can vary widely depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The nicotinic acetylcholine receptoragonist can be used singly or in combination with one or moretherapeutic agents as components of mixtures.

The pharmaceutical formulations described herein are administered to thenasal cavity of a subject. The pharmaceutical formulations describedherein include, but are not limited to, liquids, suspensions, aerosols,gels, ointments, dry powders, creams, pastes, lotions, or balms.

Pharmaceutical formulations including a nicotinic acetylcholine receptoragonist as described herein are manufactured in a conventional manner.

The pharmaceutical compositions will include a nicotinic acetylcholinereceptor agonist as described herein as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical formulations describedherein include the use of N-oxides (if appropriate), crystalline forms,amorphous phases, as well as active metabolites of these nicotinicacetylcholine receptor agonists having the same type of activity. Insome embodiments, the nicotinic acetylcholine receptor agonistsdescribed herein may exist in unsolvated form or in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the nicotinic acetylcholine receptoragonists presented herein are also considered to be disclosed herein. Insome embodiments, the compounds may exist as tautomers. All tautomersare included within the scope of the nicotinic acetylcholine receptoragonists presented herein.

In some embodiments, the nicotinic acetylcholine receptor agonists existas enantiomers, diastereomers, or other stereoisomeric forms. Thenicotinic acetylcholine receptor agonists disclosed herein include allenantiomeric, diastereomeric, and epimeric forms as well as mixturesthereof.

In certain embodiments, the pharmaceutical formulations provided hereininclude one or more preservatives to inhibit microbial activity.Suitable preservatives include mercury-containing substances such asmerfen and thiomersal; stabilized chlorine dioxide; and quaternaryammonium compounds such as benzalkonium chloride, cetyltrimethylammoniumbromide and cetylpyridinium chloride.

In some embodiments, the pharmaceutical formulations described hereinbenefit from antioxidants, metal chelating agents, thiol containingcompounds and other general stabilizing agents. Examples of suchstabilizing agents, include, but are not limited to: (a) about 0.5% toabout 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c)about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% toabout 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k)cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m)divalent cations such as magnesium and zinc; or (n) combinationsthereof.

The pharmaceutical formulations described herein, which include anicotinic acetylcholine receptor agonist, are formulated into anysuitable dosage form, including but not limited to, liquids,suspensions, aerosols, gels, ointments, dry powders, creams, pastes,lotions, or balms. The pharmaceutical formulations described herein,which include a nicotinic acetylcholine receptor agonist are formulatedinto any suitable dosage form, are administered into the nasal cavity bya syringe, dropper, bottle nebulizer, atomization pump, inhaler, powderspray device, vaporizer, patch, medicated stick, pipette, or jet ofliquid.

Combination Therapy

In certain instances, it is appropriate to administer a nicotinicacetylcholine receptor agonist in combination with another therapeuticagent.

In one embodiment, the compositions and methods described herein arealso used in conjunction with other therapeutic reagents that areselected for their particular usefulness against the condition that isbeing treated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical formulation orcomposition, and are, because of different physical and chemicalcharacteristics, administered by different routes. In one embodiment,the initial administration is made according to established protocols,and then, based upon the observed effects, the dosage, modes ofadministration and times of administration, further modified.

In various embodiments, a nicotinic acetylcholine receptor agonist, isadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,with other therapeutic reagents that are selected for their particularusefulness against the condition that is being treated. In certainembodiments, the determination of the order of administration, and thenumber of repetitions of administration of each therapeutic agent duringa treatment protocol, is based upon evaluation of the disease beingtreated and the condition of the patient.

In some embodiments, a nicotinic acetylcholine receptor agonist, isadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,with another therapeutic reagent for treating dry disease. In someembodiments, a nicotinic acetylcholine receptor agonist, is administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, with Restasis® eye drops.In some embodiments, a nicotinic acetylcholine receptor agonist, isadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,with artificial tears. In some embodiments, a nicotinic acetylcholinereceptor agonist, is administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol) orsequentially, with ocular steroids.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth.

The individual compounds of such combinations are administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. In one embodiment, the individual compounds will beadministered simultaneously in a combined pharmaceutical formulation.Appropriate doses of known therapeutic agents will be appreciated bythose skilled in the art.

The combinations referred to herein are conveniently presented for usein the form of a pharmaceutical compositions together with apharmaceutically acceptable diluent(s) or carrier(s).

Administration of a combination of agents, as used herein, includesadministration of the agents described in a single composition or in acombination therapy wherein one or more agent is administered separatelyfrom at least one other agent.

In some embodiments, a nicotinic acetylcholine receptor agonist isadministered in combination with the use of a medical device. In someembodiments, a nicotinic acetylcholine receptor agonist is administeredin combination with the use of punctal plugs.

EXAMPLES

The following specific examples are to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Example 1a Clinical Trial to Evaluate Safety and Efficacy of NasalAdministration of Nicotinic Acetylcholine Receptor Agonist Vareniclinefor Treatment of Dry Eye Disease (DED)

Purpose:

This study evaluated the use of varenicline 0.1% nasal spray (OC-01) forthe treatment of moderate to severe DED in adult patients. This studyinvestigated the safety and efficacy of using OC-01 to induce aqueoustear production and reduce the symptoms of DED.

Patients:

A total of 30 participants with moderate to severe dry eye, meeting thefollowing inclusion and exclusion criteria were enrolled.

Criteria:

Inclusion:

-   -   Males and females ≧18 years of age    -   Willing to sign the informed consent and deemed capable of        complying with the requirements of the study protocol    -   At screening visit 1, Schirmer tear test (with topical        anesthesia) of ≦10 mm/5 minutes in at least one eye;    -   At screening visit 1, Schirmer test (with topical anesthesia and        nasal stimulation with cotton swab) of at least 7 mm higher than        the unstimulated value in at least one eye;    -   Baseline Ocular Surface Disease Index score of at least 23 with        no more than 3 responses of “not applicable” at the first        screening visit    -   Normal lid/lash anatomy, blinking function and closure

Exclusion:

-   -   Chronic or recurrent epistaxis    -   Use of tobacco or nicotine products (cigarettes, cigars,        electronic cigarettes) within the past 1 year    -   Coagulation disorders that may lead to increased bleeding such        as hemophilia and thrombocytopenia    -   Lacrimal gland, nasal or sinus neoplasia or significant trauma;        prior lacrimal gland, nasal or sinus surgery or ablation leading        to denervation of the gland or nasal passages as evidenced by a        lack of response with the cotton swab nasal stimulation.    -   Severe nasal airway obstruction (e.g. severe septal deviation or        inferior turbinate hypertrophy)    -   Ocular surgery (such as refractive or cataract surgery) in        either eye within 3 months of the first screening visit;    -   A systemic condition or disease not stabilized or judged by the        investigator to be incompatible with participation in the study        (e.g. current systemic infection, uncontrolled autoimmune        disease, uncontrolled immunodeficiency disease, history of        myocardial infarction, uncontrolled hypertension, etc.) or with        the frequent assessments required by the study    -   The history or presence of any ocular disorder or condition in        either eye that would likely interfere with the interpretation        of the study results or patient safety such as a significant        corneal or conjunctival scarring, pterygium or nodular        pinguecula; current ocular infection or inflammation not        associated with dry eye; clinically significant anterior        (epithelial) basement membrane corneal dystrophy or other        clinically significant corneal dystrophy or degeneration;        clinically significant blepharitis; ocular herpetic infection,        etc.    -   Known hypersensitivity to any of the procedural agents or        materials in the study drug that contact the nasal mucosa.    -   Active or uncontrolled severe systemic allergy, chronic seasonal        allergies, rhinitis or sinusitis requiring treatment (i.e.        antihistamines, decongestants, oral or aerosol steroids) at the        time of initial screening    -   Be currently taking any medication known to cause ocular drying        (e.g., cyclosporine, antihistamines, tricyclic antidepressants,        anxiolytics, antimuscarinics, beta-blocking agents, diuretics,        phenothiazines, steroids, etc.) that has not been used on a        stable dosing regimen for 30 days prior to the first screening        visit    -   Dissolvable punctal plugs (participants with silicone plugs or        permanent occlusion of punctal ducts are eligible)    -   Active contact lens use unless discontinued at least 7 days        prior to the first screening visit and for the duration of the        study    -   Participation in any clinical trial with a new active substance        or a new device during the past 3 months    -   Women who are pregnant, planning a pregnancy or nursing at study        entry. A urine pregnancy test will be administered to women of        childbearing age.    -   Known allergies or adverse reactions to varenicline    -   Any unstable or uncontrolled cardiac, pulmonary, renal,        oncology, neurology, metabolic or other systemic condition that,        in the opinion of the investigator, would like require the        patient to seek emergent medical treatment during the course of        this study. This includes but is not limited to cardiac        arrhythmias, hypertension, coagulopathies, renal failure and        diabetes mellitus.

Inclusion/Exclusion Exceptions:

-   -   The investigator has the right to exclude any patient's        participation in the study if he/she deems it in the best        interest of the patient.    -   Minor exceptions to the inclusion/exclusion criteria should be        submitted to the sponsor and prospectively approved with the        advice of the medical monitor when required.    -   Major exceptions affecting patient safety/rights or data        validity should be reported promptly to the IRB/EC by the        investigator.

Primary Outcome:

The design of this study will enable the following measurements withrespect to OC-01 and tear production:

-   -   Change in tear production associated with a single dose of OC-01

Secondary Outcome:

The design of this study will enable the following measurements withrespect to OC-01 and tear production:

-   -   Change in tear production associated with a single dose of        vehicle    -   Change in symptoms associated with a single dose of OC-01    -   Duration of symptomatic relief associated with a single dose of        OC-01    -   Change in symptoms associated with a single dose of vehicle    -   Duration of symptomatic relief associated with a single dose of        vehicle        Together these comparisons will provide valuable information        about the safety and efficacy of OC-01 for increasing tear        production in patients with dry eye disease.

The primary safety endpoint of this study is incidence and relatednessof adverse events (AE). Descriptive statistics of adverse events will beprovided as will narratives of any serious, unexpected or drug-relatedAEs. During the study, integrity of the nasal passages will be monitoredby a suitably qualified practitioner for patient safety.

Study Design:

This study is a prospective, single-arm crossover study to evaluate thesafety and efficacy of OC-01 varenicline 0.1% nasal spray inparticipants with moderate to severe dry eye. Up to 30 participants willbe enrolled and followed for a duration of seven days.

At the first screening visit, all eligible participants will ceasetaking their current artificial tears or lubricant drops for theduration of the study and will be provided unit dose unpreservedartificial tears to be taken if their dry eye symptoms becomeintolerable. Empty unit dose vials will be collected at each study visitand counted. Patients will be instructed not to use artificial tearswithin 30 minutes of nasal drug administration or within 2 hours of astudy visit.

At the second screening visit/Study Day 0, all eligible participantswill be tested for their response two nasal formulations: OC-01 and avehicle control. Tear production will be assessed immediately prior andafter delivery of each intranasal dose using the Jones Schirmer Test inboth eyes. The order that each patient receives the OC-01 and vehicleformulation will be randomly assigned, and both the patient and examinerwill be masked to the identity of the nasal formulation. At least 90minutes following the tear production assessment, change in symptoms inresponse to delivery of each of the two nasal formulations will beassessed. The symptom assessment will be performed using awell-established environmental challenge model, the ClimaTears GoggleSystem manufactured by Biocentric Developments, LLC.

After testing on Day 0, all patients will receive a bottle of OC-01 totake home and self-administer once daily from Day 1 and Day 6. On Day 7,patients will return to the clinic where they will again be assessed fortear production and symptoms with administration of each nasalformulation.

Tear Assessments

The following ocular surface and tear film assessments will be performedin the order shown:

Ocular Surface Staining—Corneal Staining Using Fluorescein

Ocular surface staining using fluorescein and lissamine green will beassessed and recorded in the schematic representation of 5 corneal and 6conjunctival regions per eye on the case report form using the NationalEye Institute grading system. A pictorial and descriptive grading scale(grades 0 to 3) are included on the case report form (CRF).

-   1. Corneal staining should be assessed using 1.0 mg sodium    fluorescein strips.-   2. After wetting the end of the strip with a single drop of buffered    saline, the excess is shaken into a waste bin with a sharp flick.-   3. The lower lid is then pulled down and the flat end of the tip    should be gently applied to the inferior tarsal conjunctiva with the    intent of instilling a very small volume of dye and not inducing    reflex tearing.-   4. The patient will be instructed to blink naturally several times    without forced closure of the eyelid to distribute the fluorescein.-   5. After allowing fluorescein to remain on the eye for at least one    minute, the 5 corneal regions will be graded using a yellow (Wratten    #12) barrier filter in conjunction with the cobalt (blue) filter to    maximize the view of the fluorescence. The upper eyelid is lifted    slightly to grade the entire corneal surface. To enhance the    contrast, position the yellow barrier filter in the path of the    returning light (not in the path of the incident light).

Tear Film Breakup Time (TFBUT)

TFBUT will be assessed using slit lamp biomicroscopy according to thefollowing steps:

-   1. The slit-lamp will be set to a magnification of approximately    10×.-   2. With adequate fluorescein in place (preferably using DET strips),    the subject will be asked to stare straight ahead without blinking    until told otherwise. The test should be performed in a room with no    direct air on the patient's face.-   3. A stopwatch will be used to record the time between the last    complete blink and the first appearance of a growing micelle    indicating tear-film breakup.    -   Note: If the patient blinks prematurely prior to the development        of the breakup of the mires, the examiner should continue to try        to obtain a reading.-   4. Once TFBUT is observed, instruct patient to blink freely. This    test should then be repeated a second time on the same eye.-   5. If the difference between the first and second readings differs    by more than two seconds, a third measurement should be performed    and recorded.-   6. This procedure will then be performed in the other eye.-   7. It is recommended that TFBUT be performed in a room with a    temperature of approximately 18 C with a humidity of approximately    50%.

Ocular Surface Staining—Conjunctival Staining Using Lissamine Green

Ocular surface staining assessment will be completed with lissaminegreen conjunctival staining.

-   1. The lissamine green ophthalmic strip should be wetted with    buffered saline and applied to the inferior tarsal conjunctiva. Care    should be taken to instill adequate dye.-   2. After allowing lissamine green to remain on the eye for one    minute, the six nasal and temporal conjunctival regions will be    graded.-   3. To grade the temporal zone, the subject should be instructed to    look nasally; to grade the nasal zone, the subject should be    instructed to look temporally.-   4. This procedure should then be completed in the other eye.

Schirmer Test

At screening visit #1, one basal Jones Schirmer test will be performedfollowed by a Schirmer test with cotton swab nasal stimulation. TheJones Schirmer test with topical anesthetic will be used to assess tearproduction using the following steps:

-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the patient.-   2. The patient will be instructed to keep the eyes gently closed for    one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a cotton-tipped applicator.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the patient will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    patient's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF. Note: Should the Schirmer score reach maximum prior to the    5 minute endpoint, the strip can be removed and the time it took to    reach maximum recorded. However, the strip from the contralateral    eye should not be removed until it too has reached maximum score    prior to the 5 minute endpoint.-   7. As multiple Schirmer tests are performed, new anesthetic drops    should be added as necessary.

Schirmer Test Using Cotton Swab Nasal Stimulation

-   1. At screening visit #1, the Schirmer test should be performed    using cotton swab nasal stimulation. With new strips in place, the    examiner should insert cotton swabs in both participant's nostrils    simultaneously and gently probe both nasal middle turbinates for    approximately 30 seconds. After this, the examiner can simply hold    the swabs in place, applying gentle pressure, and repeat probing    intermittently as necessary.-   2. Alternatively, the participant can be instructed to hold the    cotton swabs and gently probe both nasal turbinates simultaneously,    resting intermittently before probing again. The examiner should    continuously coach the participant on how to perform this test    properly.-   3. The Schirmer strips should remain in place until five minutes    have elapsed or they have reached maximum score.    Both Schirmer scores will be recorded and verified that they meet    the inclusion criteria. As two Schirmer tests are performed, new    anesthetic drops should be instilled as necessary.    Schirmer Test with Each of Two Nasal Spray Applications    With each of the two nasal applications, the Jones Schirmer test    with topical anesthetic will be used to assess tear production using    the following steps:-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the participant    for each application.-   2. The participant will be instructed to keep the eyes gently closed    for one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a spear.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the participant will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    participant's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF.

Dry Eye Provocation and Symptom Assessment

The ClimaTears Goggle System (Biocentric Developments, LLC) will be usedto reduce periocular humidity and induce symptoms of dry eye inpatients. This system was designed for the purpose of standardizingtesting conditions for clinical studies of dry eye patients.

Patients will wear the ClimaTears Goggles continuously for up to 90 min,with their symptoms recorded via the visual analog scale (VAS) every 5minutes during the testing period. The subject will be asked to ratetheir dryness symptoms (both eyes simultaneously) by placing a verticalmark on the horizontal line to indicate the level of discomfort. 0corresponds to “no dryness” and 5 corresponds to “maximal dryness.” Theassessment line length of the scale will be 100 mm. There are manysymptoms of dry eye, including dryness, sticky feeling, burning, foreignbody sensation, itching, blurred vision, sensitivity to light, and pain.Please rate the severity of your current “dryness” symptoms (and noothers) by drawing a vertical line on the line below: (see FIG. 3).

At Day 0, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will randomly receive a dose of eitherOC-01 nasal spray or the control nasal spray, administered 2.5 minutesafter the two consecutive 45 mm measurements. Symptoms will be continuedto be monitored until the patient again reaches a score of 45 mm orhigher for two consecutive measurements, at which time the patient willreceive a second nasal dose of which ever test article they did notreceive the first time. After the second nasal dose, symptoms will bemonitored again until the patient reaches a score of a score of 45 mm orhigher for two consecutive measurements. At that time, the goggles willbe removed and the test will end. If still ongoing, the test will beterminated after 90 minutes of exposure to the goggles environment. Atthe end of this period, each patient will be asked to decide which ofthe nasal sprays made provided more relief of their dry eye symptoms.

At Day 7, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will receive a dose of the OC-01 nasalspray. Symptoms will continued to be monitored until the patient againreaches a score of 45 mm or higher for two consecutive measurements, atwhich time the goggles will be removed and the test will end. If stillongoing, the test will be terminated after 90 minutes of exposure to thegoggles environment.

Patients entering with a baseline symptoms score of more than 45 mm willhave a treatment threshold equal to this baseline score, and will thusreceive treatment after two consecutive symptoms measurements of greaterthan or equal to this value.

The instructions (in bold above) will be read to the patient before thetest begins, and before recording symptoms values immediately followingthe administration of either nasal spray.

Results of Tear Film Assessments and Dry Eye Symptoms:

Tear production in patients receiving OC-01 increased in astatitistically significant amount compared to both baseline and placebo(FIG. 1). In addition, patient reported symptoms of dry eye alsoimproved in patients receiving OC-01 versus placebo (FIG. 2).

Example 1b Clinical Trial to Evaluate Safety and Efficacy of NasalAdministration of Nicotinic Acetylcholine Receptor Agonist Cytisine forTreatment of Dry Eye Disease (DED)

Purpose:

This study evaluates the use of cytisine 0.1% nasal spray (OC-2) for thetreatment of moderate to severe DED in adult patients. This study willinvestigate the safety and efficacy of using OC-2 to induce aqueous tearproduction and reduce the symptoms of DED.

Patients:

A total of 30 participants with moderate to severe dry eye, meeting thefollowing inclusion and exclusion criteria will be enrolled.

Criteria:

Inclusion:

-   -   Males and females ≧18 years of age    -   Willing to sign the informed consent and deemed capable of        complying with the requirements of the study protocol    -   At screening visit 1, Schirmer tear test (with topical        anesthesia) of ≦10 mm/5 minutes in at least one eye;    -   At screening visit 1, Schirmer test (with topical anesthesia and        nasal stimulation with cotton swab) of at least 7 mm higher than        the unstimulated value in at least one eye;    -   Baseline Ocular Surface Disease Index score of at least 23 with        no more than 3 responses of “not applicable” at the first        screening visit    -   Normal lid/lash anatomy, blinking function and closure

Exclusion:

-   -   Chronic or recurrent epistaxis    -   Use of tobacco or nicotine products (cigarettes, cigars,        electronic cigarettes) within the past 1 year    -   Coagulation disorders that may lead to increased bleeding such        as hemophilia and thrombocytopenia    -   Lacrimal gland, nasal or sinus neoplasia or significant trauma;        prior lacrimal gland, nasal or sinus surgery or ablation leading        to denervation of the gland or nasal passages as evidenced by a        lack of response with the cotton swab nasal stimulation.    -   Severe nasal airway obstruction (e.g. severe septal deviation or        inferior turbinate hypertrophy)    -   Ocular surgery (such as refractive or cataract surgery) in        either eye within 3 months of the first screening visit;    -   A systemic condition or disease not stabilized or judged by the        investigator to be incompatible with participation in the study        (e.g. current systemic infection, uncontrolled autoimmune        disease, uncontrolled immunodeficiency disease, history of        myocardial infarction, uncontrolled hypertension, etc.) or with        the frequent assessments required by the study    -   The history or presence of any ocular disorder or condition in        either eye that would likely interfere with the interpretation        of the study results or patient safety such as a significant        corneal or conjunctival scarring, pterygium or nodular        pinguecula; current ocular infection or inflammation not        associated with dry eye; clinically significant anterior        (epithelial) basement membrane corneal dystrophy or other        clinically significant corneal dystrophy or degeneration;        clinically significant blepharitis; ocular herpetic infection,        etc.    -   Known hypersensitivity to any of the procedural agents or        materials in the study drug that contact the nasal mucosa.    -   Active or uncontrolled severe systemic allergy, chronic seasonal        allergies, rhinitis or sinusitis requiring treatment (i.e.        antihistamines, decongestants, oral or aerosol steroids) at the        time of initial screening    -   Be currently taking any medication known to cause ocular drying        (e.g., cyclosporine, antihistamines, tricyclic antidepressants,        anxiolytics, antimuscarinics, beta-blocking agents, diuretics,        phenothiazines, steroids, etc.) that has not been used on a        stable dosing regimen for 30 days prior to the first screening        visit    -   Dissolvable punctal plugs (participants with silicone plugs or        permanent occlusion of punctal ducts are eligible)    -   Active contact lens use unless discontinued at least 7 days        prior to the first screening visit and for the duration of the        study    -   Participation in any clinical trial with a new active substance        or a new device during the past 3 months    -   Women who are pregnant, planning a pregnancy or nursing at study        entry. A urine pregnancy test will be administered to women of        childbearing age.    -   Known allergies or adverse reactions to cytisine    -   Any unstable or uncontrolled cardiac, pulmonary, renal,        oncology, neurology, metabolic or other systemic condition that,        in the opinion of the investigator, would like require the        patient to seek emergent medical treatment during the course of        this study. This includes but is not limited to cardiac        arrhythmias, hypertension, coagulopathies, renal failure and        diabetes mellitus.

Inclusion/Exclusion Exceptions:

-   -   The investigator has the right to exclude any patient's        participation in the study if he/she deems it in the best        interest of the patient.    -   Minor exceptions to the inclusion/exclusion criteria should be        submitted to the sponsor and prospectively approved with the        advice of the medical monitor when required.    -   Major exceptions affecting patient safety/rights or data        validity should be reported promptly to the IRB/EC by the        investigator.

Primary Outcome:

The design of this study will enable the following measurements withrespect to OC-2 and tear production:

-   -   Change in tear production associated with a single dose of OC-2

Secondary Outcome:

The design of this study will enable the following measurements withrespect to OC-2 and tear production:

-   -   Change in tear production associated with a single dose of        vehicle    -   Change in symptoms associated with a single dose of OC-2    -   Duration of symptomatic relief associated with a single dose of        OC-2    -   Change in symptoms associated with a single dose of vehicle    -   Duration of symptomatic relief associated with a single dose of        vehicle        Together these comparisons will provide valuable information        about the safety and efficacy of OC-2 for increasing tear        production in patients with dry eye disease.

The primary safety endpoint of this study is incidence and relatednessof adverse events (AE). Descriptive statistics of adverse events will beprovided as will narratives of any serious, unexpected or drug-relatedAEs. During the study, integrity of the nasal passages will be monitoredby a suitably qualified practitioner for patient safety.

Study Design:

This study is a prospective, single-arm crossover study to evaluate thesafety and efficacy of OC-2 cytisine 0.1% nasal spray in participantswith moderate to severe dry eye. Up to 30 participants will be enrolledand followed for a duration of seven days.

At the first screening visit, all eligible participants will ceasetaking their current artificial tears or lubricant drops for theduration of the study and will be provided unit dose unpreservedartificial tears to be taken if their dry eye symptoms becomeintolerable. Empty unit dose vials will be collected at each study visitand counted. Patients will be instructed not to use artificial tearswithin 30 minutes of nasal drug administration or within 2 hours of astudy visit.

At the second screening visit/Study Day 0, all eligible participantswill be tested for their response two nasal formulations: OC-2 and avehicle control. Tear production will be assessed immediately prior andafter delivery of each intranasal dose using the Jones Schirmer Test inboth eyes. The order that each patient receives the OC-2 and vehicleformulation will be randomly assigned, and both the patient and examinerwill be masked to the identity of the nasal formulation. At least 90minutes following the tear production assessment, change in symptoms inresponse to delivery of each of the two nasal formulations will beassessed. The symptom assessment will be performed using awell-established environmental challenge model, the ClimaTears GoggleSystem manufactured by Biocentric Developments, LLC.

After testing on Day 0, all patients will receive a bottle of OC-2 totake home and self-administer once daily from Day 1 and Day 6. On Day 7,patients will return to the clinic where they will again be assessed fortear production and symptoms with administration of each nasalformulation.

Tear Assessments

The following ocular surface and tear film assessments will be performedin the order shown:

Ocular Surface Staining—Corneal Staining Using Fluorescein

Ocular surface staining using fluorescein and lissamine green will beassessed and recorded in the schematic representation of 5 corneal and 6conjunctival regions per eye on the case report form using the NationalEye Institute grading system. A pictorial and descriptive grading scale(grades 0 to 3) are included on the case report form (CRF).

-   1. Corneal staining should be assessed using 1.0 mg sodium    fluorescein strips.-   2. After wetting the end of the strip with a single drop of buffered    saline, the excess is shaken into a waste bin with a sharp flick.-   3. The lower lid is then pulled down and the flat end of the tip    should be gently applied to the inferior tarsal conjunctiva with the    intent of instilling a very small volume of dye and not inducing    reflex tearing.-   4. The patient will be instructed to blink naturally several times    without forced closure of the eyelid to distribute the fluorescein.-   5. After allowing fluorescein to remain on the eye for at least one    minute, the 5 corneal regions will be graded using a yellow (Wratten    #12) barrier filter in conjunction with the cobalt (blue) filter to    maximize the view of the fluorescence. The upper eyelid is lifted    slightly to grade the entire corneal surface. To enhance the    contrast, position the yellow barrier filter in the path of the    returning light (not in the path of the incident light).

Tear Film Breakup Time (TFBUT)

TFBUT will be assessed using slit lamp biomicroscopy according to thefollowing steps:

-   1. The slit-lamp will be set to a magnification of approximately    10×.-   2. With adequate fluorescein in place (preferably using DET strips),    the subject will be asked to stare straight ahead without blinking    until told otherwise. The test should be performed in a room with no    direct air on the patient's face.-   3. A stopwatch will be used to record the time between the last    complete blink and the first appearance of a growing micelle    indicating tear-film breakup.    -   Note: If the patient blinks prematurely prior to the development        of the breakup of the mires, the examiner should continue to try        to obtain a reading.-   4. Once TFBUT is observed, instruct patient to blink freely. This    test should then be repeated a second time on the same eye.-   5. If the difference between the first and second readings differs    by more than two seconds, a third measurement should be performed    and recorded.-   6. This procedure will then be performed in the other eye.-   7. It is recommended that TFBUT be performed in a room with a    temperature of approximately 18 C with a humidity of approximately    50%.

Ocular Surface Staining—Conjunctival Staining Using Lissamine Green

Ocular surface staining assessment will be completed with lissaminegreen conjunctival staining.

-   1. The lissamine green ophthalmic strip should be wetted with    buffered saline and applied to the inferior tarsal conjunctiva. Care    should be taken to instill adequate dye.-   2. After allowing lissamine green to remain on the eye for one    minute, the six nasal and temporal conjunctival regions will be    graded.-   3. To grade the temporal zone, the subject should be instructed to    look nasally; to grade the nasal zone, the subject should be    instructed to look temporally.-   4. This procedure should then be completed in the other eye.

Schirmer Test

At screening visit #1, one basal Jones Schirmer test will be performedfollowed by a Schirmer test with cotton swab nasal stimulation. TheJones Schirmer test with topical anesthetic will be used to assess tearproduction using the following steps:

-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the patient.-   2. The patient will be instructed to keep the eyes gently closed for    one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a cotton-tipped applicator.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the patient will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    patient's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF. Note: Should the Schirmer score reach maximum prior to the    5 minute endpoint, the strip can be removed and the time it took to    reach maximum recorded. However, the strip from the contralateral    eye should not be removed until it too has reached maximum score    prior to the 5 minute endpoint.-   7. As multiple Schirmer tests are performed, new anesthetic drops    should be added as necessary.

Schirmer Test Using Cotton Swab Nasal Stimulation

-   1. At screening visit #1, the Schirmer test should be performed    using cotton swab nasal stimulation. With new strips in place, the    examiner should insert cotton swabs in both participant's nostrils    simultaneously and gently probe both nasal middle turbinates for    approximately 30 seconds. After this, the examiner can simply hold    the swabs in place, applying gentle pressure, and repeat probing    intermittently as necessary.-   2. Alternatively, the participant can be instructed to hold the    cotton swabs and gently probe both nasal turbinates simultaneously,    resting intermittently before probing again. The examiner should    continuously coach the participant on how to perform this test    properly.-   3. The Schirmer strips should remain in place until five minutes    have elapsed or they have reached maximum score.    Both Schirmer scores will be recorded and verified that they meet    the inclusion criteria. As two Schirmer tests are performed, new    anesthetic drops should be instilled as necessary.    Schirmer Test with Each of Two Nasal Spray Applications    With each of the two nasal applications, the Jones Schirmer test    with topical anesthetic will be used to assess tear production using    the following steps:-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the participant    for each application.-   2. The participant will be instructed to keep the eyes gently closed    for one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a spear.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the participant will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    participant's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF.

Dry Eye Provocation and Symptom Assessment

The ClimaTears Goggle System (Biocentric Developments, LLC) will be usedto reduce periocular humidity and induce symptoms of dry eye inpatients. This system was designed for the purpose of standardizingtesting conditions for clinical studies of dry eye patients.

Patients will wear the ClimaTears Goggles continuously for up to 90 min,with their symptoms recorded via the visual analog scale (VAS) every 5minutes during the testing period. The subject will be asked to ratetheir dryness symptoms (both eyes simultaneously) by placing a verticalmark on the horizontal line to indicate the level of discomfort. 0corresponds to “no dryness” and 5 corresponds to “maximal dryness.” Theassessment line length of the scale will be 100 mm. There are manysymptoms of dry eye, including dryness, sticky feeling, burning, foreignbody sensation, itching, blurred vision, sensitivity to light, and pain.Please rate the severity of your current “dryness” symptoms (and noothers) by drawing a vertical line on the line below: (see FIG. 3).

At Day 0, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will randomly receive a dose of eitherOC-2 nasal spray or the control nasal spray, administered 2.5 minutesafter the two consecutive 45 mm measurements. Symptoms will be continuedto be monitored until the patient again reaches a score of 45 mm orhigher for two consecutive measurements, at which time the patient willreceive a second nasal dose of which ever test article they did notreceive the first time. After the second nasal dose, symptoms will bemonitored again until the patient reaches a score of a score of 45 mm orhigher for two consecutive measurements. At that time, the goggles willbe removed and the test will end. If still ongoing, the test will beterminated after 90 minutes of exposure to the goggles environment. Atthe end of this period, each patient will be asked to decide which ofthe nasal sprays made provided more relief of their dry eye symptoms.

At Day 7, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will receive a dose of the OC-2 nasalspray. Symptoms will continued to be monitored until the patient againreaches a score of 45 mm or higher for two consecutive measurements, atwhich time the goggles will be removed and the test will end. If stillongoing, the test will be terminated after 90 minutes of exposure to thegoggles environment.

Patients entering with a baseline symptoms score of more than 45 mm willhave a treatment threshold equal to this baseline score, and will thusreceive treatment after two consecutive symptoms measurements of greaterthan or equal to this value.

The instructions (in bold above) will be read to the patient before thetest begins, and before recording symptoms values immediately followingthe administration of either nasal spray.

Example 1c Clinical Trial to Evaluate Safety and Efficacy of NasalAdministration of Nicotinic Acetylcholine Receptor Agonist Epibatidinefor Treatment of Dry Eye Disease (DED)

Purpose:

This study evaluates the use of epibatidine 0.1% nasal spray (OC-03) forthe treatment of moderate to severe DED in adult patients. This studywill investigate the safety and efficacy of using OC-03 to induceaqueous tear production and reduce the symptoms of DED.

Patients:

A total of 30 participants with moderate to severe dry eye, meeting thefollowing inclusion and exclusion criteria will be enrolled.

Criteria:

Inclusion:

-   -   Males and females ≧18 years of age    -   Willing to sign the informed consent and deemed capable of        complying with the requirements of the study protocol    -   At screening visit 1, Schirmer tear test (with topical        anesthesia) of ≦10 mm/5 minutes in at least one eye;    -   At screening visit 1, Schirmer test (with topical anesthesia and        nasal stimulation with cotton swab) of at least 7 mm higher than        the unstimulated value in at least one eye;    -   Baseline Ocular Surface Disease Index score of at least 23 with        no more than 3 responses of “not applicable” at the first        screening visit    -   Normal lid/lash anatomy, blinking function and closure

Exclusion:

-   -   Chronic or recurrent epistaxis    -   Use of tobacco or nicotine products (cigarettes, cigars,        electronic cigarettes) within the past 1 year    -   Coagulation disorders that may lead to increased bleeding such        as hemophilia and thrombocytopenia    -   Lacrimal gland, nasal or sinus neoplasia or significant trauma;        prior lacrimal gland, nasal or sinus surgery or ablation leading        to denervation of the gland or nasal passages as evidenced by a        lack of response with the cotton swab nasal stimulation.    -   Severe nasal airway obstruction (e.g. severe septal deviation or        inferior turbinate hypertrophy)    -   Ocular surgery (such as refractive or cataract surgery) in        either eye within 3 months of the first screening visit;    -   A systemic condition or disease not stabilized or judged by the        investigator to be incompatible with participation in the study        (e.g. current systemic infection, uncontrolled autoimmune        disease, uncontrolled immunodeficiency disease, history of        myocardial infarction, uncontrolled hypertension, etc.) or with        the frequent assessments required by the study    -   The history or presence of any ocular disorder or condition in        either eye that would likely interfere with the interpretation        of the study results or patient safety such as a significant        corneal or conjunctival scarring, pterygium or nodular        pinguecula; current ocular infection or inflammation not        associated with dry eye; clinically significant anterior        (epithelial) basement membrane corneal dystrophy or other        clinically significant corneal dystrophy or degeneration;        clinically significant blepharitis; ocular herpetic infection,        etc.    -   Known hypersensitivity to any of the procedural agents or        materials in the study drug that contact the nasal mucosa.    -   Active or uncontrolled severe systemic allergy, chronic seasonal        allergies, rhinitis or sinusitis requiring treatment (i.e.        antihistamines, decongestants, oral or aerosol steroids) at the        time of initial screening    -   Be currently taking any medication known to cause ocular drying        (e.g., cyclosporine, antihistamines, tricyclic antidepressants,        anxiolytics, antimuscarinics, beta-blocking agents, diuretics,        phenothiazines, steroids, etc.) that has not been used on a        stable dosing regimen for 30 days prior to the first screening        visit    -   Dissolvable punctal plugs (participants with silicone plugs or        permanent occlusion of punctal ducts are eligible)    -   Active contact lens use unless discontinued at least 7 days        prior to the first screening visit and for the duration of the        study    -   Participation in any clinical trial with a new active substance        or a new device during the past 3 months    -   Women who are pregnant, planning a pregnancy or nursing at study        entry. A urine pregnancy test will be administered to women of        childbearing age.    -   Known allergies or adverse reactions to epibatidine    -   Any unstable or uncontrolled cardiac, pulmonary, renal,        oncology, neurology, metabolic or other systemic condition that,        in the opinion of the investigator, would like require the        patient to seek emergent medical treatment during the course of        this study. This includes but is not limited to cardiac        arrhythmias, hypertension, coagulopathies, renal failure and        diabetes mellitus.

Inclusion/Exclusion Exceptions:

-   -   The investigator has the right to exclude any patient's        participation in the study if he/she deems it in the best        interest of the patient.    -   Minor exceptions to the inclusion/exclusion criteria should be        submitted to the sponsor and prospectively approved with the        advice of the medical monitor when required.    -   Major exceptions affecting patient safety/rights or data        validity should be reported promptly to the IRB/EC by the        investigator.

Primary Outcome:

The design of this study will enable the following measurements withrespect to OC-03 and tear production:

-   -   Change in tear production associated with a single dose of OC-03

Secondary Outcome:

The design of this study will enable the following measurements withrespect to OC-03 and tear production:

-   -   Change in tear production associated with a single dose of        vehicle    -   Change in symptoms associated with a single dose of OC-03    -   Duration of symptomatic relief associated with a single dose of        OC-03    -   Change in symptoms associated with a single dose of vehicle    -   Duration of symptomatic relief associated with a single dose of        vehicle        Together these comparisons will provide valuable information        about the safety and efficacy of OC-03 for increasing tear        production in patients with dry eye disease.

The primary safety endpoint of this study is incidence and relatednessof adverse events (AE). Descriptive statistics of adverse events will beprovided as will narratives of any serious, unexpected or drug-relatedAEs. During the study, integrity of the nasal passages will be monitoredby a suitably qualified practitioner for patient safety.

Study Design:

This study is a prospective, single-arm crossover study to evaluate thesafety and efficacy of OC-03 epibatidine 0.1% nasal spray inparticipants with moderate to severe dry eye. Up to 30 participants willbe enrolled and followed for a duration of seven days.

At the first screening visit, all eligible participants will ceasetaking their current artificial tears or lubricant drops for theduration of the study and will be provided unit dose unpreservedartificial tears to be taken if their dry eye symptoms becomeintolerable. Empty unit dose vials will be collected at each study visitand counted. Patients will be instructed not to use artificial tearswithin 30 minutes of nasal drug administration or within 2 hours of astudy visit.

At the second screening visit/Study Day 0, all eligible participantswill be tested for their response two nasal formulations: OC-03 and avehicle control. Tear production will be assessed immediately prior andafter delivery of each intranasal dose using the Jones Schirmer Test inboth eyes. The order that each patient receives the OC-03 and vehicleformulation will be randomly assigned, and both the patient and examinerwill be masked to the identity of the nasal formulation. At least 90minutes following the tear production assessment, change in symptoms inresponse to delivery of each of the two nasal formulations will beassessed. The symptom assessment will be performed using awell-established environmental challenge model, the ClimaTears GoggleSystem manufactured by Biocentric Developments, LLC.

After testing on Day 0, all patients will receive a bottle of OC-03 totake home and self-administer once daily from Day 1 and Day 6. On Day 7,patients will return to the clinic where they will again be assessed fortear production and symptoms with administration of each nasalformulation.

Tear Assessments

The following ocular surface and tear film assessments will be performedin the order shown:

Ocular Surface Staining—Corneal Staining Using Fluorescein

Ocular surface staining using fluorescein and lissamine green will beassessed and recorded in the schematic representation of 5 corneal and 6conjunctival regions per eye on the case report form using the NationalEye Institute grading system. A pictorial and descriptive grading scale(grades 0 to 3) are included on the case report form (CRF).

-   1. Corneal staining should be assessed using 1.0 mg sodium    fluorescein strips.-   2. After wetting the end of the strip with a single drop of buffered    saline, the excess is shaken into a waste bin with a sharp flick.-   3. The lower lid is then pulled down and the flat end of the tip    should be gently applied to the inferior tarsal conjunctiva with the    intent of instilling a very small volume of dye and not inducing    reflex tearing.-   4. The patient will be instructed to blink naturally several times    without forced closure of the eyelid to distribute the fluorescein.-   5. After allowing fluorescein to remain on the eye for at least one    minute, the 5 corneal regions will be graded using a yellow (Wratten    #12) barrier filter in conjunction with the cobalt (blue) filter to    maximize the view of the fluorescence. The upper eyelid is lifted    slightly to grade the entire corneal surface. To enhance the    contrast, position the yellow barrier filter in the path of the    returning light (not in the path of the incident light).

Tear Film Breakup Time (TFBUT)

TFBUT will be assessed using slit lamp biomicroscopy according to thefollowing steps:

-   1. The slit-lamp will be set to a magnification of approximately    10×.-   2. With adequate fluorescein in place (preferably using DET strips),    the subject will be asked to stare straight ahead without blinking    until told otherwise. The test should be performed in a room with no    direct air on the patient's face.-   3. A stopwatch will be used to record the time between the last    complete blink and the first appearance of a growing micelle    indicating tear-film breakup.    -   Note: If the patient blinks prematurely prior to the development        of the breakup of the mires, the examiner should continue to try        to obtain a reading.-   4. Once TFBUT is observed, instruct patient to blink freely. This    test should then be repeated a second time on the same eye.-   5. If the difference between the first and second readings differs    by more than two seconds, a third measurement should be performed    and recorded.-   6. This procedure will then be performed in the other eye.-   7. It is recommended that TFBUT be performed in a room with a    temperature of approximately 18 C with a humidity of approximately    50%.

Ocular Surface Staining—Conjunctival Staining Using Lissamine Green

Ocular surface staining assessment will be completed with lissaminegreen conjunctival staining.

-   1. The lissamine green ophthalmic strip should be wetted with    buffered saline and applied to the inferior tarsal conjunctiva. Care    should be taken to instill adequate dye.-   2. After allowing lissamine green to remain on the eye for one    minute, the six nasal and temporal conjunctival regions will be    graded.-   3. To grade the temporal zone, the subject should be instructed to    look nasally; to grade the nasal zone, the subject should be    instructed to look temporally.-   4. This procedure should then be completed in the other eye.

Schirmer Test

At screening visit #1, one basal Jones Schirmer test will be performedfollowed by a Schirmer test with cotton swab nasal stimulation. TheJones Schirmer test with topical anesthetic will be used to assess tearproduction using the following steps:

-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the patient.-   2. The patient will be instructed to keep the eyes gently closed for    one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a cotton-tipped applicator.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the patient will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    patient's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF. Note: Should the Schirmer score reach maximum prior to the    5 minute endpoint, the strip can be removed and the time it took to    reach maximum recorded. However, the strip from the contralateral    eye should not be removed until it too has reached maximum score    prior to the 5 minute endpoint.-   7. As multiple Schirmer tests are performed, new anesthetic drops    should be added as necessary.

Schirmer Test Using Cotton Swab Nasal Stimulation

-   1. At screening visit #1, the Schirmer test should be performed    using cotton swab nasal stimulation. With new strips in place, the    examiner should insert cotton swabs in both participant's nostrils    simultaneously and gently probe both nasal middle turbinates for    approximately 30 seconds. After this, the examiner can simply hold    the swabs in place, applying gentle pressure, and repeat probing    intermittently as necessary.-   2. Alternatively, the participant can be instructed to hold the    cotton swabs and gently probe both nasal turbinates simultaneously,    resting intermittently before probing again. The examiner should    continuously coach the participant on how to perform this test    properly.-   3. The Schirmer strips should remain in place until five minutes    have elapsed or they have reached maximum score.    Both Schirmer scores will be recorded and verified that they meet    the inclusion criteria. As two Schirmer tests are performed, new    anesthetic drops should be instilled as necessary.    Schirmer Test with Each of Two Nasal Spray Applications    With each of the two nasal applications, the Jones Schirmer test    with topical anesthetic will be used to assess tear production using    the following steps:-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the participant    for each application.-   2. The participant will be instructed to keep the eyes gently closed    for one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a spear.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the participant will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    participant's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF.

Dry Eye Provocation and Symptom Assessment

The ClimaTears Goggle System (Biocentric Developments, LLC) will be usedto reduce periocular humidity and induce symptoms of dry eye inpatients. This system was designed for the purpose of standardizingtesting conditions for clinical studies of dry eye patients.

Patients will wear the ClimaTears Goggles continuously for up to 90 min,with their symptoms recorded via the visual analog scale (VAS) every 5minutes during the testing period. The subject will be asked to ratetheir dryness symptoms (both eyes simultaneously) by placing a verticalmark on the horizontal line to indicate the level of discomfort. 0corresponds to “no dryness” and 5 corresponds to “maximal dryness.” Theassessment line length of the scale will be 100 mm. There are manysymptoms of dry eye, including dryness, sticky feeling, burning, foreignbody sensation, itching, blurred vision, sensitivity to light, and pain.Please rate the severity of your current “dryness” symptoms (and noothers) by drawing a vertical line on the line below: (see FIG. 3).

At Day 0, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will randomly receive a dose of eitherOC-03 nasal spray or the control nasal spray, administered 2.5 minutesafter the two consecutive 45 mm measurements. Symptoms will be continuedto be monitored until the patient again reaches a score of 45 mm orhigher for two consecutive measurements, at which time the patient willreceive a second nasal dose of which ever test article they did notreceive the first time. After the second nasal dose, symptoms will bemonitored again until the patient reaches a score of a score of 45 mm orhigher for two consecutive measurements. At that time, the goggles willbe removed and the test will end. If still ongoing, the test will beterminated after 90 minutes of exposure to the goggles environment. Atthe end of this period, each patient will be asked to decide which ofthe nasal sprays made provided more relief of their dry eye symptoms.

At Day 7, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will receive a dose of the OC-03 nasalspray. Symptoms will continued to be monitored until the patient againreaches a score of 45 mm or higher for two consecutive measurements, atwhich time the goggles will be removed and the test will end. If stillongoing, the test will be terminated after 90 minutes of exposure to thegoggles environment.

Patients entering with a baseline symptoms score of more than 45 mm willhave a treatment threshold equal to this baseline score, and will thusreceive treatment after two consecutive symptoms measurements of greaterthan or equal to this value.

The instructions (in bold above) will be read to the patient before thetest begins, and before recording symptoms values immediately followingthe administration of either nasal spray.

Example 1d Clinical Trial to Evaluate Safety and Efficacy of NasalAdministration of Nicotinic Acetylcholine Receptor Agonist Tebaniclinefor Treatment of Dry Eye Disease (DED)

Purpose:

This study evaluates the use of tebanicline 0.1% nasal spray (OC-04) forthe treatment of moderate to severe DED in adult patients. This studywill investigate the safety and efficacy of using OC-04 to induceaqueous tear production and reduce the symptoms of DED.

Patients:

A total of 30 participants with moderate to severe dry eye, meeting thefollowing inclusion and exclusion criteria will be enrolled.

Criteria:

Inclusion:

-   -   Males and females ≧18 years of age    -   Willing to sign the informed consent and deemed capable of        complying with the requirements of the study protocol    -   At screening visit 1, Schirmer tear test (with topical        anesthesia) of ≦10 mm/5 minutes in at least one eye;    -   At screening visit 1, Schirmer test (with topical anesthesia and        nasal stimulation with cotton swab) of at least 7 mm higher than        the unstimulated value in at least one eye;    -   Baseline Ocular Surface Disease Index score of at least 23 with        no more than 3 responses of “not applicable” at the first        screening visit    -   Normal lid/lash anatomy, blinking function and closure

Exclusion:

-   -   Chronic or recurrent epistaxis    -   Use of tobacco or nicotine products (cigarettes, cigars,        electronic cigarettes) within the past 1 year    -   Coagulation disorders that may lead to increased bleeding such        as hemophilia and thrombocytopenia    -   Lacrimal gland, nasal or sinus neoplasia or significant trauma;        prior lacrimal gland, nasal or sinus surgery or ablation leading        to denervation of the gland or nasal passages as evidenced by a        lack of response with the cotton swab nasal stimulation.    -   Severe nasal airway obstruction (e.g. severe septal deviation or        inferior turbinate hypertrophy)    -   Ocular surgery (such as refractive or cataract surgery) in        either eye within 3 months of the first screening visit;    -   A systemic condition or disease not stabilized or judged by the        investigator to be incompatible with participation in the study        (e.g. current systemic infection, uncontrolled autoimmune        disease, uncontrolled immunodeficiency disease, history of        myocardial infarction, uncontrolled hypertension, etc.) or with        the frequent assessments required by the study    -   The history or presence of any ocular disorder or condition in        either eye that would likely interfere with the interpretation        of the study results or patient safety such as a significant        corneal or conjunctival scarring, pterygium or nodular        pinguecula; current ocular infection or inflammation not        associated with dry eye; clinically significant anterior        (epithelial) basement membrane corneal dystrophy or other        clinically significant corneal dystrophy or degeneration;        clinically significant blepharitis; ocular herpetic infection,        etc.    -   Known hypersensitivity to any of the procedural agents or        materials in the study drug that contact the nasal mucosa.    -   Active or uncontrolled severe systemic allergy, chronic seasonal        allergies, rhinitis or sinusitis requiring treatment (i.e.        antihistamines, decongestants, oral or aerosol steroids) at the        time of initial screening    -   Be currently taking any medication known to cause ocular drying        (e.g., cyclosporine, antihistamines, tricyclic antidepressants,        anxiolytics, antimuscarinics, beta-blocking agents, diuretics,        phenothiazines, steroids, etc.) that has not been used on a        stable dosing regimen for 30 days prior to the first screening        visit    -   Dissolvable punctal plugs (participants with silicone plugs or        permanent occlusion of punctal ducts are eligible)    -   Active contact lens use unless discontinued at least 7 days        prior to the first screening visit and for the duration of the        study    -   Participation in any clinical trial with a new active substance        or a new device during the past 3 months    -   Women who are pregnant, planning a pregnancy or nursing at study        entry. A urine pregnancy test will be administered to women of        childbearing age.    -   Known allergies or adverse reactions to tebanicline    -   Any unstable or uncontrolled cardiac, pulmonary, renal,        oncology, neurology, metabolic or other systemic condition that,        in the opinion of the investigator, would like require the        patient to seek emergent medical treatment during the course of        this study. This includes but is not limited to cardiac        arrhythmias, hypertension, coagulopathies, renal failure and        diabetes mellitus.

Inclusion/Exclusion Exceptions:

-   -   The investigator has the right to exclude any patient's        participation in the study if he/she deems it in the best        interest of the patient.    -   Minor exceptions to the inclusion/exclusion criteria should be        submitted to the sponsor and prospectively approved with the        advice of the medical monitor when required.    -   Major exceptions affecting patient safety/rights or data        validity should be reported promptly to the IRB/EC by the        investigator.

Primary Outcome:

The design of this study will enable the following measurements withrespect to OC-04 and tear production:

-   -   Change in tear production associated with a single dose of OC-04

Secondary Outcome:

The design of this study will enable the following measurements withrespect to OC-04 and tear production:

-   -   Change in tear production associated with a single dose of        vehicle    -   Change in symptoms associated with a single dose of OC-04    -   Duration of symptomatic relief associated with a single dose of        OC-04    -   Change in symptoms associated with a single dose of vehicle    -   Duration of symptomatic relief associated with a single dose of        vehicle        Together these comparisons will provide valuable information        about the safety and efficacy of OC-04 for increasing tear        production in patients with dry eye disease.

The primary safety endpoint of this study is incidence and relatednessof adverse events (AE). Descriptive statistics of adverse events will beprovided as will narratives of any serious, unexpected or drug-relatedAEs. During the study, integrity of the nasal passages will be monitoredby a suitably qualified practitioner for patient safety.

Study Design:

This study is a prospective, single-arm crossover study to evaluate thesafety and efficacy of OC-04 tebanicline 0.1% nasal spray inparticipants with moderate to severe dry eye. Up to 30 participants willbe enrolled and followed for a duration of seven days.

At the first screening visit, all eligible participants will ceasetaking their current artificial tears or lubricant drops for theduration of the study and will be provided unit dose unpreservedartificial tears to be taken if their dry eye symptoms becomeintolerable. Empty unit dose vials will be collected at each study visitand counted. Patients will be instructed not to use artificial tearswithin 30 minutes of nasal drug administration or within 2 hours of astudy visit.

At the second screening visit/Study Day 0, all eligible participantswill be tested for their response two nasal formulations: OC-04 and avehicle control. Tear production will be assessed immediately prior andafter delivery of each intranasal dose using the Jones Schirmer Test inboth eyes. The order that each patient receives the OC-04 and vehicleformulation will be randomly assigned, and both the patient and examinerwill be masked to the identity of the nasal formulation. At least 90minutes following the tear production assessment, change in symptoms inresponse to delivery of each of the two nasal formulations will beassessed. The symptom assessment will be performed using awell-established environmental challenge model, the ClimaTears GoggleSystem manufactured by Biocentric Developments, LLC.

After testing on Day 0, all patients will receive a bottle of OC-04 totake home and self-administer once daily from Day 1 and Day 6. On Day 7,patients will return to the clinic where they will again be assessed fortear production and symptoms with administration of each nasalformulation.

Tear Assessments

The following ocular surface and tear film assessments will be performedin the order shown:

Ocular Surface Staining—Corneal Staining Using Fluorescein

Ocular surface staining using fluorescein and lissamine green will beassessed and recorded in the schematic representation of 5 corneal and 6conjunctival regions per eye on the case report form using the NationalEye Institute grading system. A pictorial and descriptive grading scale(grades 0 to 3) are included on the case report form (CRF).

-   1. Corneal staining should be assessed using 1.0 mg sodium    fluorescein strips.-   2. After wetting the end of the strip with a single drop of buffered    saline, the excess is shaken into a waste bin with a sharp flick.-   3. The lower lid is then pulled down and the flat end of the tip    should be gently applied to the inferior tarsal conjunctiva with the    intent of instilling a very small volume of dye and not inducing    reflex tearing.-   4. The patient will be instructed to blink naturally several times    without forced closure of the eyelid to distribute the fluorescein.-   5. After allowing fluorescein to remain on the eye for at least one    minute, the 5 corneal regions will be graded using a yellow (Wratten    #12) barrier filter in conjunction with the cobalt (blue) filter to    maximize the view of the fluorescence. The upper eyelid is lifted    slightly to grade the entire corneal surface. To enhance the    contrast, position the yellow barrier filter in the path of the    returning light (not in the path of the incident light).

Tear Film Breakup Time (TFBUT)

TFBUT will be assessed using slit lamp biomicroscopy according to thefollowing steps:

-   1. The slit-lamp will be set to a magnification of approximately    10×.-   2. With adequate fluorescein in place (preferably using DET strips),    the subject will be asked to stare straight ahead without blinking    until told otherwise. The test should be performed in a room with no    direct air on the patient's face.-   3. A stopwatch will be used to record the time between the last    complete blink and the first appearance of a growing micelle    indicating tear-film breakup.    -   Note: If the patient blinks prematurely prior to the development        of the breakup of the mires, the examiner should continue to try        to obtain a reading.-   4. Once TFBUT is observed, instruct patient to blink freely. This    test should then be repeated a second time on the same eye.-   5. If the difference between the first and second readings differs    by more than two seconds, a third measurement should be performed    and recorded.-   6. This procedure will then be performed in the other eye.-   7. It is recommended that TFBUT be performed in a room with a    temperature of approximately 18 C with a humidity of approximately    50%.

Ocular Surface Staining—Conjunctival Staining Using Lissamine Green

Ocular surface staining assessment will be completed with lissaminegreen conjunctival staining.

-   1. The lissamine green ophthalmic strip should be wetted with    buffered saline and applied to the inferior tarsal conjunctiva. Care    should be taken to instill adequate dye.-   2. After allowing lissamine green to remain on the eye for one    minute, the six nasal and temporal conjunctival regions will be    graded.-   3. To grade the temporal zone, the subject should be instructed to    look nasally; to grade the nasal zone, the subject should be    instructed to look temporally.-   4. This procedure should then be completed in the other eye.

Schirmer Test

At screening visit #1, one basal Jones Schirmer test will be performedfollowed by a Schirmer test with cotton swab nasal stimulation. TheJones Schirmer test with topical anesthetic will be used to assess tearproduction using the following steps:

-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the patient.-   2. The patient will be instructed to keep the eyes gently closed for    one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a cotton-tipped applicator.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the patient will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    patient's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF. Note: Should the Schirmer score reach maximum prior to the    5 minute endpoint, the strip can be removed and the time it took to    reach maximum recorded. However, the strip from the contralateral    eye should not be removed until it too has reached maximum score    prior to the 5 minute endpoint.-   7. As multiple Schirmer tests are performed, new anesthetic drops    should be added as necessary.

Schirmer Test Using Cotton Swab Nasal Stimulation

-   1. At screening visit #1, the Schirmer test should be performed    using cotton swab nasal stimulation. With new strips in place, the    examiner should insert cotton swabs in both participant's nostrils    simultaneously and gently probe both nasal middle turbinates for    approximately 30 seconds. After this, the examiner can simply hold    the swabs in place, applying gentle pressure, and repeat probing    intermittently as necessary.-   2. Alternatively, the participant can be instructed to hold the    cotton swabs and gently probe both nasal turbinates simultaneously,    resting intermittently before probing again. The examiner should    continuously coach the participant on how to perform this test    properly.-   3. The Schirmer strips should remain in place until five minutes    have elapsed or they have reached maximum score.    Both Schirmer scores will be recorded and verified that they meet    the inclusion criteria. As two Schirmer tests are performed, new    anesthetic drops should be instilled as necessary.    Schirmer Test with Each of Two Nasal Spray Applications    With each of the two nasal applications, the Jones Schirmer test    with topical anesthetic will be used to assess tear production using    the following steps:-   1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride    or equivalent should be instilled in both eyes of the participant    for each application.-   2. The participant will be instructed to keep the eyes gently closed    for one minute.-   3. After opening the eyes and allowing the eyes to recover for    approximately one additional minute, excess moisture in the inferior    fornix is gently removed with a spear.-   4. Schirmer strips (35 mm×5 mm size filter paper strip) will be    placed in each eye at the junction of the middle and lateral thirds    of the lower eye lid.-   5. Under ambient light, the participant will be instructed to look    forward and to blink normally during the course of the test. The    test should be performed in a room with no direct air on the    participant's face.-   6. After five minutes, strips will be removed from both eyes and the    amount of wetting will be recorded. The strips should be taped to    the CRF.

Dry Eye Provocation and Symptom Assessment

The ClimaTears Goggle System (Biocentric Developments, LLC) will be usedto reduce periocular humidity and induce symptoms of dry eye inpatients. This system was designed for the purpose of standardizingtesting conditions for clinical studies of dry eye patients.

Patients will wear the ClimaTears Goggles continuously for up to 90 min,with their symptoms recorded via the visual analog scale (VAS) every 5minutes during the testing period. The subject will be asked to ratetheir dryness symptoms (both eyes simultaneously) by placing a verticalmark on the horizontal line to indicate the level of discomfort. 0corresponds to “no dryness” and 5 corresponds to “maximal dryness.” Theassessment line length of the scale will be 100 mm. There are manysymptoms of dry eye, including dryness, sticky feeling, burning, foreignbody sensation, itching, blurred vision, sensitivity to light, and pain.Please rate the severity of your current “dryness” symptoms (and noothers) by drawing a vertical line on the line below: (see FIG. 3).

At Day 0, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will randomly receive a dose of eitherOC-04 nasal spray or the control nasal spray, administered 2.5 minutesafter the two consecutive 45 mm measurements. Symptoms will be continuedto be monitored until the patient again reaches a score of 45 mm orhigher for two consecutive measurements, at which time the patient willreceive a second nasal dose of which ever test article they did notreceive the first time. After the second nasal dose, symptoms will bemonitored again until the patient reaches a score of a score of 45 mm orhigher for two consecutive measurements. At that time, the goggles willbe removed and the test will end. If still ongoing, the test will beterminated after 90 minutes of exposure to the goggles environment. Atthe end of this period, each patient will be asked to decide which ofthe nasal sprays made provided more relief of their dry eye symptoms.

At Day 7, patients will begin wearing the goggles and be monitored untilthey reach a symptom score of 45 mm or more for two consecutivemeasurements, at which time they will receive a dose of the OC-04 nasalspray. Symptoms will continued to be monitored until the patient againreaches a score of 45 mm or higher for two consecutive measurements, atwhich time the goggles will be removed and the test will end. If stillongoing, the test will be terminated after 90 minutes of exposure to thegoggles environment.

Patients entering with a baseline symptoms score of more than 45 mm willhave a treatment threshold equal to this baseline score, and will thusreceive treatment after two consecutive symptoms measurements of greaterthan or equal to this value.

The instructions (in bold above) will be read to the patient before thetest begins, and before recording symptoms values immediately followingthe administration of either nasal spray.

Example 2 OC-01 Formulation

OC-01 contains 0.1% varenicline in sterile phosphate buffered saline(PBS) consisting of 137 mM sodium chloride, 2.7 mM potassium chlorideand 10 mM phosphate buffer at pH 7.4 without preservatives. Theformulation was packaged in a 20 mL opaque polyethylene nasal spraybottle that delivers a unit dose of 50 microliters. The vehicle controlwas supplied in the identical packaging. Both OC-01 and vehicle arelabeled with a code denoting the contents of the package, which will notbe known to the participants or masked study personnel.

Example 3 Additional Pharmaceutical Formulations

To prepare pharmaceutical formulations suitable for administrationintranasally, 10 mg of a nicotinic acetylcholine receptor agonist isdissolved in 10 mL of a specified vehicle. 1 mL of this solution isdiluted in 9 mL of vehicle to afford a “0.1× dilution” formulation.Following the first dilution, 1 mL of the “0.1× dilution” formulation isdiluted in 9 mL of vehicle to afford a “0.01× dilution” formulation. Thethree formulations with varying concentrations of the nicotinicacetylcholine receptor agonist are stored at 4° C.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of increasing tear production, comprising the local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, wherein the agonist selectively binds to the peripheral nicotinic acetylcholine receptor.
 2. The method of claim 1, wherein the agonist does not cross the blood-brain barrier in a pharmacologically relevant concentration.
 3. The method of claim 1, wherein the agonist selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2, and alpha7.
 4. The method of claim 1, wherein the agonist is administered in an amount that is not systemically bioavailable.
 5. The method of claim 1, wherein the agonist selectively binds to the peripheral nicotinic acetylcholine receptor in an amount that does not result in undesired psychoactive side effects.
 6. The method of claim 1, wherein the agonist selectively binds to the peripheral nicotinic acetylcholine receptor in an amount that does not result in undesired systemic side effects.
 7. The method of claim 1, further comprising the local administration of one or more substances that prevent the entry or reduce the entry of the nicotinic acetylcholine receptor into the desensitized state, or facilitate the recovery of the nicotinic acetylcholine receptor from the desensitized state.
 8. The method of claim 7, wherein the one or more substances are selected from protein kinase C (PKC) or factors that upregulate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or up-modulate PKA, and calcineurin inhibitors.
 9. The method of claim 8, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus.
 10. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is selected from cytisine, epibatidine, varenicline, tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380.
 11. The method of claim 1, wherein at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity.
 12. The method of claim 1, wherein at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity.
 13. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is administered at least once daily.
 14. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is administered at least twice daily.
 15. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is administered at least once weekly.
 16. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is administered into the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm.
 17. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is administered into the nasal cavity by a syringe, dropper, bottle nebulizer, atomization pump, inhaler, powder spray device, vaporizer, patch, medicated stick, pipette, or jet of liquid.
 18. The method of claim 1, wherein the trigeminal nerve is activated.
 19. The method of claim 18, wherein the anterior ethmoidal nerve is activated.
 20. The method of claim 1, wherein the nasolacrimal reflex is activated. 